CH646173A5 - THIA AZA CONNECTIONS WITH BETA LACTAMRING. - Google Patents

Description

The present invention relates to new bicyclic thia-aza compounds containing a 3-position unsubstituted β-lactam ring with antibiotic properties.

Since the discovery of penicillin, numerous bicyclic thia-aza compounds with a β-lactam structure have become known. An overview of previous work is given by E.H. Flynn "Cephalosporins and Penicillins", Academic Press, New York and London, 1972. Recent developments are from J.Cs. Jâszberényi et al., Progr. Med. Chem. Vol. 12 1975, 395-477, and P.G. Sammes, Chem. Rev. 1976, Vol. 76, No. 1 113-155. At the symposium “Recent Advances in the Chemistry of ß-Lactam Antibiotics” in Cambridge, England, from June 28 to 30, 1976, R.B. Woodward 6-acylamino-2-penem-3-carboxylic acid compounds with antibiotic effects described the novel

2 penem ring system included.

In addition to the usual penam and cephem compounds which carry an acylamino group in the 6- or 7-position, there have also become known those which are unsubstituted in these positions, e.g. 3-carboxy-2,2-dimethylpenam (J.P. Clayton, J. Chem. Soc., 1969,2123) and 3-methyl-4-carboxy-

3-cephem (K. Kühlein, Liebigs Ann., 1974, p. 369 and D. Bormann, ibid., P. 1391). However, no significant antibiotic activity is known of these compounds. No 2-penem compounds unsubstituted in the 6-position have so far become known.

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The object of the present invention is to produce bicyclic thia-aza compounds containing β-lactam ring which have the 2-penem ring system which is unsubstituted in the 6-position and which are active against both normal and resistant germs.

The inventive production of the novel compounds, as well as the new intermediates required for this, also open up new fields in which research can be carried out for further, technically usable compounds.

The ring system of the compounds of the present invention has the formula

15

20th

and can be systematically referred to as 7-C) xo-4-thia-l-azabicyclo [3,2,0] hept-2-ene. For the sake of simplicity, it will be referred to as "2-penem" in the following, the following numbering being used in penicillin chemistry and derived from the Penam:

)

5 '

30th

0;

The 2-penem ring system has an asymmetrically substituted carbon atom in the 5-position, so that corresponding compounds, according to the Cahn-Ingold-Prelog name in the (5R) -, (5S) - or the racemic (5R, S) configuration -tion can occur.

The present invention relates to 2-penem-3-carboxylic acid compounds of the formula

H

0:

r \

40

45

50

C-R,

N "1

xc <

I.

0 »C-R2

./

(I),

where R, represents hydrogen, an organic radical connected via a carbon atom to the ring carbon atom or an etherified mercapto group, and R2 represents hydroxyl or a radical RA2 forming an esterified carboxyl group together with the carbonyl group -C (= O) - 1-oxides thereof, as well as salts of such compounds with salt-forming groups, process for the preparation of 65 such compounds, furthermore pharmaceutical preparations containing compounds of formula I with pharmacological properties, and the use of the new compounds either as pharmacologically active substances, preferably in the form of pharmaceutical preparations, or as Intermediates.

An organic radical R] which is connected to the ring carbon atom via a carbon atom is primarily an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or aliphatic hydrocarbon radical with up to 18, preferably up to 10, carbon atoms, in particular optionally substituted lower alkyl , optionally functionally modified carboxyl, cycloalkyl, cycloalkyl-lower alkyl, phenyl, naphthyl or phenyl-lower alkyl. Substituents of such residues are e.g. optionally functionally modified, such as etherified or esterified hydroxy or mercapto groups, e.g. Hydroxy, lower alkoxy, e.g. Methoxy or ethoxy, lower alkanoyloxy, e.g. Acetyloxy or propionyloxy, halogen, e.g. Chlorine or bromine, or lower alkylthio, e.g. Methylthio or tert. Butylthio, or optionally functionally modified carboxyl groups, such as carboxyl, lower alkoxycarbonyl, e.g. Methoxycarbonyl or ethoxycarbonyl, carbamoyl or cyan, further nitro or optionally, as by lower alkyl, e.g. Methyl or ethyl, mono- or disubstituted, or by lower alkylene, e.g. 1,4-butylene or 1,5-pentylene, disubstituted or protected, such as acylated, amino.

A lower alkyl group R] contains e.g. up to 7, in particular up to 4 carbon atoms, and is i.a. Methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, tert-butyl or pentyl. Substituted lower alkyl is primarily substituted methyl or in 1 or in particular in the () position, substituted ethyl or propyl, such as hydroxymethyl or hydroxyethyl, lower alkoxymethyl or lower alkoxyethyl, for example methoxymethyl or methoxyethyl, lower alkanoyloxymethyl or lower alkanoyloxyethyl, for example acetyloxymethyl, propion -methyl or acetyloxyethyl, halomethyl or haloethyl, for example chloromethyl or bromomethyl or chloromethyl or bromoethyl, lower alkylthiomethyl or lower alkylthioethyl, such as methylthiomethyl, tert Cyanoethyl, or optionally protected, for example protected by a half ester of carbonic acid, such as tert-butoxycarbonyl, benzyloxycarbonyl or p-nitrobenzyloxycarbonyl, or acylated, such as by optionally substituted acetyl, such as Phenoxyacetyl, acylated aminomethyl, aminoethyl or aminopropyl.

An optionally functionally modified carboxyl group Ri is a free or one of the esterified carboxyl groups mentioned under the groups -C (= 0) -RA2 or an amidated carboxyl group, such as lower alkoxycarbonyl, e.g. Methoxy, ethoxy or tert. -Butoxycarbonyl, arylnie-deralkoxycarbonyl, such as benzyloxy-, p-nitrobenzyloxy- or diphenylmethoxycarbonyl, aryloxycarbonyl, such as optionally e.g. phenyloxycarbonyl substituted by halogen, such as chlorine, lower alkoxy, such as methoxy, or nitro, such as phenyloxycarbonyl, o-, m- or p-chlorophenyloxy-, penta-chlorophenyloxycarbonyl-, o-, m- or p-methoxyphenyloxy- or p-nitrophenyloxycarbonyl , Aminocarbonyl or substituted, such as by lower alkyl, for example Methyl or ethyl, mono * or disubstituted aminocarbonyl.

A cycloalkyl radical R] has e.g. 3 to 7 carbon atoms and is e.g. Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, while a cycloalkyl-lower alkyl radical R contains, for example, 4 to 7 carbon atoms and e.g. Cyclo-propylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

646173

A phenyl, naphthyl, e.g. 1- or 2-naphthyl, or a phenyl-lower alkyl, e.g. Benzyl or 1- or 2-phenylethyl radical R] can, preferably in the aromatic radical, e.g. by lower alkyl, such as methyl or ethyl, lower alkoxy, such as methoxy, or halogen, such as fluorine or chlorine, furthermore by nitro, amino or substituted amino, such as di-lower alkylamino, e.g. Dimethylamino.

A radical Rj can also represent a heterocyclic or heterocyclic-aliphatic radical, preferably aromatic, which is bonded via a carbon atom, such as one having 5 or 6 ring members and nitrogen, oxygen or sulfur as heteroatoms, such as pyridyl, e.g. 2-, 3- or 4-pyridyl, thienyl, e.g. 2-thienyl, or furyl, e.g. 2-furyl, or a corresponding pyridyl, thienyl or furyl-lower alkyl, especially methyl, represent.

An etherified mercapto group Rj is etherified by an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical having up to 18, preferably up to 10 carbon atoms, and is in particular optionally substituted lower alkylthio, lower alkenylthio, cycloalk-yl Cycloalkyl-lower alkylthio, phenylthio or phenyl-lower alkylthio. Substituents of such residues are e.g. optionally functionally modified such as optionally etherified or esterified hydroxy or mercapto, e.g. Hydroxy, lower alkoxy, e.g. Methoxy or ethoxy, lower alkanoyloxy, e.g. Acetyloxy or propionyloxy, halogen, e.g. Chlorine or bromine, or lower alkyl mercapto, e.g. Meth-ylthio, or optionally functionally modified carboxyl groups, such as carboxyl, lower alkoxycarbonyl, e.g. Methoxycarbonyl or ethoxycarbonyl, carbamoyl or cyano, further nitro or optionally, as by lower alkyl, e.g. Methyl or ethyl by acyl such as lower alkanoyl e.g. Acetyl, mono- or disubstituted, or by lower alkylene, e.g. 1,4-butylene or 1,5-pentylene disubstituted amino.

A lower alkylthio radical R] contains up to 7, in particular up to 4, carbon atoms and is e.g. Methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert. Butylthio or pentylthio. Substituted lower alkylthio Rj is primarily substituted methylthio, ethylthio or propylthio, where substituents are in the 1-, 2- or 3-position, such as methoxymethylthio, ethoxymethylthio, methoxyethylthio, or methoxypropylthio, lower alkanoyloxy-methylthio, lower alkanoxyloxyethylthio, such as acetoxymethylthio, acetoxyethylthio or acetoxypropylthio, halomethylthio, haloethylthio or halopropylthio, for example Chloro or bromoethyl thio or chloro or bromopropylthio, lower alkoxycarbonylmethylthio or lower alkoxycarbonylethylthio, e.g. Methoxycarbonylethylthio, cyanomethylthio, cyanoethylthio or optionally protected e.g. acetylated, aminomethylthio, aminoethylthio or aminopropylthio.

A lower alkenylthio radical R [contains 2 to 7, in particular 2 to 4, carbon atoms and is in particular 1-lower alkenylthio, e.g. Vinylthio, 1-propenylthio, butenylthio or

1-pentenylthio or 2-lower alkenylthio, e.g. Allylthio. Substituted lower alkenylthio R, is primarily in

Substituted 2-position, the substituents being in particular lower alkoxy, lower alkanoyloxy and optionally protected amino, and is, for example, 2-methoxyvinylthio, 2-acetoxyvinylthio, 2-acetylaminovin-ylthio or appropriately substituted 1-propenylthio.

A cycloalkylthio group R [e.g. 3 to 7 carbon atoms and is e.g. Cyclopropylthio, Cyclobutylthio, Cyclopentylthio or Cyclohexylthio.

A cycloalkyl-lower alkylthio radical R] has e.g. 4 to 7 carbon atoms and is e.g. Cyclopropylmethylthio, Cyclobut-ylmethylthio, Cyclopentylmethylthio or Cyclohexylmeth-ylthio.

5 A phenylthio or a phenyl-lower alkylthio, e.g. Benzyl or 1- or 2-phenylethylthio radical Ri can preferably be present in the aromatic radical, e.g. by lower alkyl, such as methyl or ethyl, lower alkoxy, such as methoxy, halogen, such as fluorine or chlorine, nitro or amino, io In an esterified carboxyl group of the formula -C (= 0) -RA2, Ra2 is primarily one by an organic Rest or an organic silyl or stannyl group etherified hydroxy group. Organic radicals, also as substituents in organic silyl or stannyl groups, are aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic radicals, in particular optionally substituted hydrocarbon radicals of this type, and also heterocyclic or heterocyclic-aliphatic radicals, preferably with up to 18 Carbon atoms.

20 An etherified hydroxy group RÄ2 forms together with the carbonyl grouping a, preferably easily cleavable, e.g. reductive, such as hydrogenolytic, or solvolytic, such as acidolytic or in particular basic or neutral hydrolytic, as well as oxidatively or under physiological conditions cleavable, or easily convertible into another esterified carboxyl group, esterified carboxyl group. Such a group Ra2 is e.g. 2-halogeno-lower alkoxy, where halogen preferably has an atomic weight above 19, e.g. 2,2,2-trichloroethoxy or 2-iodoethoxy, furthermore 2-chloroethoxy 30 or 2-bromoethoxy, which can easily be converted into the latter, or 2-lower alkylsulfonyl-lower alkoxy, e.g. 2-methyl-sulfonylethoxy. The group RA2 is furthermore an optionally substituted hydrocarbon radical, in particular saturated aliphatic or aromatic hydrocarbon radicals, such as lower alkyl, e.g. Methyl and / or phenyl, polysubstituted methoxy group or one substituted by an unsaturated aliphatic hydrocarbon residue such as lower alkenyl e.g.

1-lower alkenyl, such as vinyl, by a carbocyclic aryl group or having an electron-donating substituent

40 mono-substituted methoxy group, such as tert-lower alkoxy, e.g., by a heterocyclic group of aromatic character having an oxygen or sulfur as a ring member. tert-butyloxy or tert-pentyloxy, optionally substituted diphenylmethoxy, e.g. Diphenylmethoxy or 45 4,4: dimethoxydiphenylmethoxy, lower alkenyloxy, especially 2-lower alkenyloxy, e.g. Allyloxy, lower alkoxy-phenyl-lower alkoxy, e.g. Lower alkoxy-benzyloxy, such as meth-oxybenzyloxy (where methoxy is primarily in the 3-, 4- and / or 5-position), primarily 3- or 4-methoxy-50-benzyloxy, 3,4: dimethoxybenzyloxy, or before all nitro-benzyloxy, e.g. 4-nitrobenzyloxy, 2-nitrobenzyloxy or 4,5-dimethoxy-2-nitro-benzyloxy, or furfuryloxy, such as

2-furfuryloxy. The group RA2 is also a 2-oxoethoxy group which may be in the 2-position by lower alkyl,

55 such as methyl, lower alkoxy, such as methoxy or ethoxy, by aralkyl, such as benzyl, or by aryl, such as phenyl, and in

1-position is substituted by lower alkyl, such as methyl, lower alkoxycarbonyl, such as methoxycarbonyl, lower alkylcarbonyl, such as methylcarbonyl, aralkylcarbonyl, such as benzylcarbonyl or arylcarbonyl, such as benzoyl, and represents, for example, acetonyloxy, phenacyloxy, 2,4-dioxo-3-pentyloxy , l-methoxycarbonyl-2-oxo-propyloxy or 1-ethoxy-carbonyl-2-oxo-propyloxy. The group RA2 is also one

2-cyanoethoxy group, which is optionally substituted in the 1- and / or in the 2-position, for example by lower alkyl, such as methyl, or aryl, such as optionally substituted phenyl, and represents, for example, 2-cyanoethoxy or 2-cyano-2phenyl

60

646 173 6

ethoxy represents. RA2 is also a 2- (SI) (S2) (S3) -silylethoxy salts are in particular those of compounds of the group in which the substituents Sb S2 and S3 and formula I with an acidic grouping, such as a carboxy depending on one another each an optionally substituted group, primarily metal or ammonium salts, such as Al hydrocarbon radical, and the individual radicals potassium metal and alkaline earth metal, for example Sodium, potassium, can be linked by a simple C-C bond. A s magnesium or calcium salts, as well as ammonium salts with hydrocarbon radical Sb S2 and S3 is, for example, an Al ammonia or suitable organic amines, in which alkyl, cycloalkyl or aryl radical, preferably one with primarily aliphatic, cycloaliphatic, cycloaliphatic, at most 12 Carbon atoms, the rest of one type of aliphatic and araliphatic primary, secondary or tertiary by a residue of another type or by lower alkoxy, aromatic mono-, di- or polyamines, and heterocyclic bases such as methoxy, or halogen, such as fluorine or chlorine, substi - 10 come into consideration for salt formation, such as lower alkylamines, and is in particular lower alkyl with up to, for example Triethylamine, hydroxy-lower alkylamines, e.g. 2-hydr-7, preferably up to 4 carbon atoms, such as methyl, ethyl, oxyethylamine, di- (2-hydroxyethyl) amine, or tri- (2-hydropropyl or butyl, cycloalkyl with up to 7 carbon oxyethyl) amine, basic aliphatic esters of carboxylic groups, such as cyclopropyl or cyclohexyl, cycloalkylalkyl, such as ren, for example 4-aminobenzoic acid-2-diethylamino-ethyl ester, cyclopentylmethyl, aryl with up to 10 carbon atoms, 15 lower alkylene amines, e.g. 1-ethyl piperidine, cycloalkyl such as phenyl, tolyl or xylyl, aryl lower alkyl such as benzyl amines, e.g. Bicyclohexylamine, or benzylamines, e.g.

or phenylethyl. To be emphasized residues RA2 of this type N, N'-dibenzylethylenediamine, furthermore bases of the pyridine type are 2-tri-lower alkylsilylethoxy, such as 2-trimethylsilylethoxy e.g. Pyridine, collidine or quinoline. Compounds of the foroder 2- (dibutyl-methyl-silyl) ethoxy, and 2-triarylsilyl ether I which have a basic group can also be oxy, such as 2-triphenylsilyl ethoxy. 20 acid addition salts, e.g. with inorganic acids, such as

Hydrochloric acid, sulfuric acid or phosphoric acid, or with

Ra2 can also be 2-oxa- or 2-thia-cycloalkoxy or -cyten organic carbon or sulfonic acids, e.g. Triflu

clo-alkenyloxy with 5-7 ring members, such as 2-tetrahydrofuran or acetic acid or p-toluenesulfonic acid. Compounds yloxy, 2-tetrahydropyranyloxy or 2,3-dihydro-2-pyran of the formula I with an acidic and a basic group yloxy or a corresponding thia group or RA2-25 can also be in the form of internal salts, i.e. in zwitterioni-

together with the -C (= 0) grouping there is an activated shear form. 1-oxides of compounds of the formula

Ester group and is for example nitrophenyloxy, e.g. I with salt-forming groups can also form salts, such as 4-nitrophenyloxy or 2,4-dinitrophenyloxy, or polyhalo as described above. Preferred are pharmaceutically

genphenyloxy, e.g. Pentachlorophenyloxy. However, RA2 can contain acceptable salts.

also unbranched lower alkoxy, e.g. Methoxy or ethoxy30 The penem compounds of formula I can be because of that. asymmetric carbon atom in 5-position in the (5R) -,

An organic silyloxy or organic stannyloxy (5S) or in the (5 R, S) configuration. Preferred group Ra2 is in particular one through 1 to 3, optionally the (5R) compounds.

substituted hydrocarbon radicals, preferably with up to

18 carbon atoms, substituted silyloxy or stannyl 3S. The compounds of the present invention have oxy group. As a substituent, it preferably contains useful pharmacological properties or can optionally be substituted, for example by lower alkoxy, used as intermediates for the preparation of those such as methoxy, or substituted by halogen, such as chlorine. Compounds of the formula I in which R] has the abovementioned

has aliphatic, cycloaliphatic, aromatic or araliphatic meaning, and R2 or one together with the car

hydrocarbon residues such as lower alkyl, halogeno-40-one, preferably under physiological conditions

lower alkyl, cycloalkyl, phenyl or phenyl-lower alkyl, and form easily cleavable, esterified carboxyl group-forming tri-lower alkylsilyloxy, e.g. Trimethylsil etherified hydroxy group RA2 means, or pharmacological

yloxy, halogen-lower alkoxy-lower alkylsilyloxy, e.g. Chlorologically acceptable salts of such compounds with salt

groups forming methoxy-methyl-silyloxy, or tri-lower alkylstannyloxy, for example inhibit growth e.g. Trin-n-butylstannyloxy. 45 of gram-positive and gram-negative germs, such as Staphy-

The RA2 group can also contain etherified hydroxy lococcus aureus and penicillin-resistant Staphylococcus au-

group, which together with the carbonyl grouping reus, Escherichia coli, Proteus vulgaris, Pseudomonas aerugi-

-C (= O) - a nosa and Pseudomonas aeruginosa R. cleavable under physiological conditions

esterified carboxyl group, primarily forms an acyl group.

oxymethoxy group, where acyl e.g. the rest of an organic compound of the formula I in the above-mentioned germs with a carboxylic acid, primarily an optionally sub-0.5% solution on filter paper (6 mm in diameter)

substituted lower alkane carboxylic acid, or in which zones of inhibition of about 16 to 33 mm in diameter have been determined,

Acyloxymethyl forms the remainder of a lactone. For example, while penicillin V tested analogously at normal

Hydroxy groups are lower alkanoyloxy methoxy, e.g. len Staphylococcus aureus germination zones from 31 to 32

Acetyloxymethyloxy or pivaloyloxymethoxy, aminonia-mm in diameter and resistant to germs of only 10 to deralkanoylmethoxy, especially a-amino-lower alkanoyl-11 mm.

oxymethoxy, e.g. Glycyloxymethoxy, L-Valyloxymethoxy, The compounds of formula I according to the invention are

L-leucyloxymethoxy, also phthalidyloxy. Effective in other phy-in vitro in the following dose ranges: against cocci, siologically cleavable ester groups -C (= 0) -RA2 is RA2 a 6Q (including penicillinase formers) of <0.1 to 64 mcg / ml,

2-aminoethyloxy group, in which amino is derived from two lower gene enterobate groups (including β-lactamase formers) of alkyl or, where appropriate, alkyne-containing 0.5 to 128 mcg / ml and against Pseudomonas aeruginosa of 2

len is substituted, and for example 2-dimethylamino ether to 128 mcg / ml. In vivo (mouse) with subtle application

oxy, 2-diethylaminoethoxy or 2- (1-morpholino) ethoxy cation against Streptococcus in a dose range of 8 to represents. 65 50 mg / kg effective.

Preferred groups RA2 are those which are neutral, and in particular the activity against basic or under physiological conditions in Pseudomonas aeruginosa, against which neither penicillin V nor a free hydroxyl group can be transferred. Penicillin G is effective.

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The compounds inhibit ß-lactamase and act synergistically in combination with other ß-lactamantibiotics.

These new compounds, particularly the preferred ones, or their pharmacologically acceptable salts, can therefore be e.g. in the form of antibiotic preparations, for the treatment of the human or animal body in the case of corresponding system or organ infections, furthermore as feed additives, for the preservation of foods or as disinfectants. io

1-oxides of compounds of formula I, wherein R | and R2 have the meanings given in connection with the formula I, or compounds of the formula I in which R has the meaning given above, and R2 for one, together with the —C (= 0) —group one, preferably easily 15, cleavable represents esterified carboxyl group radical RA2, where such an esterified carboxyl group is different from a physiologically cleavable carboxyl group, are valuable intermediates which can be obtained in a simple manner, for example as described below, can be converted into the above pharmacologically active compounds.

The invention particularly relates to the 2-penem compounds of the formula I in which R, hydrogen, optionally by etherified or esterified hydroxy or mercapto, such as lower alkoxy, lower alkanoyloxy or lower alkylthio 25, by functionally modified carboxyl, such as lower alkoxycarbonyl, or by optionally substituted, e.g. acylated, amino, substituted lower alkyl, or phenyl or phenyl-lower alkyl substituted by lower alkyl, lower alkoxy, halogen, nitro, amino or di-lower alkylamino, an aromatic heterocyclic radical, or an etherified mercapto group, such as lower alkylthio, and R2 for hydroxyl, for a by is an organic radical or an organic silyl or stannyl group, basic neutral or physiologically cleavable etherified hydr-35 oxy group RA2, and of such compounds with salt-forming groups.

Primarily in a 2-penem compound of the formula I or in a salt of such a compound with salt-forming groups R | for hydrogen, lower alkyl with 40 up to 7 carbon atoms, e.g. Methyl, isopropyl or pentyl, lower alkoxy lower alkyl, wherein lower alkyl each contains up to 4 carbon atoms, e.g. Methoxymethyl, lower alkanoyloxy lower alkyl, wherein lower alkyl each contains up to 4 carbon atoms, e.g. Acetyloxymethyl, 45

Lower alkylthio-lower alkyl, wherein lower alkyl each contains up to 4 carbon atoms, e.g. Methylthiomethyl or tert. Butylthiomethyl, lower alkoxy-carbonyl-lower alkyl, in which lower alkyl each contains up to 4 carbon atoms, such as lower alkoxycarbonylmethyl or lower alkoxycarbonyl-50 ethyl, e.g. Methoxycarbonylethyl, amino lower alkyl wherein lower alkyl contains up to 4 carbon atoms and wherein the amino group is optionally acylated by a half ester of carbonic acid or by a substituted acetyl group, e.g. Aminomethyl, aminoethyl or aminopropyl, or corresponding phenyl substituted by benzylcarbonyl, p-nitrobenzyloxycarbonyl or phenoxyacetyl N-acylated aminomethyl, ethyl or propyl, or optionally substituted by lower alkyl, halogen, nitro, amino or di-lower alkylamino, e.g. Phenyl, or dimethylaminophenyl, phenyl-lower alkyl, e.g. Benzyl, an aromatic heterocyclyl radical containing 5 or 6 ring members with a nitrogen, an oxygen or a sulfur atom as the hetero atom, e.g. Pyridyl, furyl or thienyl, or lower alkylthio, e.g. Ethylthio, and R2 for hydroxy, or for a basic, neutral or physiologically cleavable etherified hydroxy group, such as optionally a-polybranched lower alkoxy, e.g.

tert-butyloxy, 2-substituted 2-oxoethoxy, e.g. Acetonyloxy or phenacyloxy, 2-cyanoethoxy, 2- (S1) (S2) (S3) -silylethoxy, where Sb S2 and S3 are each lower alkyl, such as methyl, or phenyl, such as 2-trimethylsilylethoxy or 2-triphenylsilylethoxy, 1-phenyl-lower alkoxy with 1-3, optionally by lower alkoxy and / or substituted phenyl radicals, for example 4-methoxybenzyloxy, 4-nitrobenzyloxy, 2-Ni-tro-4,5-dimethoxy-benzyloxy, diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or trityloxy, lower alkanoyl-oxymethoxy, e.g. Acetyloxymethoxy or pivaloyloxymethoxy, a-amino lower alkanoyloxymethoxy, e.g. Glycyloxymethoxy, 2-phthalidyloxy, pentachlorophenyloxy, further tri-lower alkylsilyloxy, e.g. Trimethylsilyloxy, as well as lower alkenyloxy, especially 2-lower alkenyloxy, e.g. Allyloxy.

The invention relates primarily to 2-penem compounds of the formula I, in which R] is hydrogen, lower alkyl having up to 5 carbon atoms, such as methyl, isopropyl, or pentyl, lower alkoxy lower alkyl having up to 4 carbon atoms, e.g. Methoxymethyl, or lower alkynoyloxy lower alkyl having up to 4 carbon atoms, e.g. Acetyloxymethyl, lower alkylthione lower alkyl having up to 5 carbon atoms, e.g. Methylthiomethyl or tert-butylthiomethyl, lower alkoxy-carbonyl-lower alkyl having up to 5 carbon atoms, e.g. 2-methoxycarbonylethyl, optionally benzyloxycarbonyl, p-nitrobenzyloxycarbonyl or phenoxyacetyl, N-acylated amino lower alkyl, such as aminomethyl, 2-aminoethyl-3 or aminopropyl, optionally substituted by dimethylamino phenyl, benzyl, pyridyl, e.g. 2-, 4- or especially 3-pyridyl, furyl, e.g. 3-furyl or especially 2-furyl or thienyl e.g. 3- or especially 2-thienyl, or lower alkylthio with up to 4 carbon atoms, e.g. Ethylthio means, and R2 primarily for hydroxy, furthermore for the above-mentioned basic, neutral or physiologically cleavable etherified hydroxy groups, in particular for p-nitrobenzyloxy or acetonyloxy, and salts, in particular pharmacologically acceptable, non-toxic salts, of such compounds salt-forming groups, such as the alkali metal, for example Sodium, or alkaline earth metal, e.g. Calcium salts, or ammonium salts, including those with amines, of compounds of the formula I in which R2 is hydroxy.

The invention relates primarily to 2-R! -2-penem-3-car-bonic acid compounds, in which Rj is hydrogen, methyl, pentyl, acetyloxymethyl, tert-butylthiomethyl,

2-methoxycarbonylethyl, 2-aminoethyl, 3-aminopropyl, phenoxyacetylaminomethyl, 3- (2-phenoxyacetylamino) propyl, phenyl, 3-dimethylaminophenyl, benzyl, 2-furyl,

Is 3-pyridyl or ethylthio, and the salts, especially the pharmacologically acceptable salts of such compounds having salt-forming groups.

The new compounds can be prepared by using a ylide compound of the formula

(II)

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in which Z represents oxygen or sulfur and R] and RA2 have the meanings given above, and in which X® denotes either a triply substituted phosphoniogroup or a doubly esterified phosphonogroup together with a cation, optionally with intermediate protection of the functional groups, and optionally closes one obtained A compound having a salt-forming group is converted into a salt or a salt obtained into the free compound or another salt.

In the starting material of formula II, Ri is in particular one of the preferred, optionally substituted hydrocarbon radicals, functional groups usually being in protected form, amino e.g. are present in acylated or also in the form of the nitro or azido group.

In a starting material of the formula II, RA2 preferably represents an etherified hydroxyl group with the -C (= 0) grouping, which forms an esterified carboxyl group, which is easily cleavable, especially under mild conditions, with any functional groups present in an esterified carboxyl group known way, eg can be protected as indicated above. A group Ra2 is among others Lower alkoxy, especially a-poly branched lower alkoxy, e.g. Methoxy or tert-butyloxy, lower alkenyloxy, especially 2-lower alkenyloxy, e.g. Allyloxy, or 2-halo-lower alkoxy, e.g. 2,2,2-trichloroethoxy, 2-bromoethoxy, or 2-iodoethoxy, 2-lower alkylsulfonyl-nederalkoxy, e.g. 2-methylsulfonylethoxy, or an optionally substituted one such as lower alkoxy, e.g. 1-phenyl-lower alkoxy group containing methoxy or nitro, such as optionally e.g. as indicated, substituted benzyloxy or diphenylmethoxy, e.g. Benzyloxy, 4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy or 4,4'-dimethoxy-di-phenylmethoxy, pentachlorophenyloxy, acetonyloxy, 2-cyano-ethoxy, a 2- (S]) (S2) (S3) -silylethoxy group, such as 2-trimethylsilylethoxy, 2- (dibutylmethylsilyl) ethoxy or 2-triphenylsilylethoxy, also an organic silyloxy or stannyloxy group, such as tri-lower alkylsilyloxy, for example Trimeth-ylsilyloxy, or one of the physiologically cleavable etherified hydroxy groups mentioned.

Group X® in the starting material of the formula II is one of the phosphonio or phosphono groups customary in the Wittig condensation reaction, in particular a triaryl, e.g. Triphenyl, or tri lower alkyl, e.g. Tributyl phosphono group, or one through lower alkyl, e.g. Ethyl, doubly esterified phosphono group, the symbol X® for the case of the phosphono group additionally the cation of a strong base, especially a suitable metal such as alkali metal, e.g. Lithium, sodium or potassium ion. Preferred as Group X® are triphenylphosphonio on the one hand and diethylphosphono on the other hand together with an alkali metal, e.g. Sodium ion.

In phosphonium compounds of the formula II, which are also referred to as phosphorane compounds in the isomeric ylene form, the negative charge is neutralized by the positively charged phosphonio group. In phosphono compounds of the formula II, which can also be referred to in their isomeric form as phosphonate compounds, the negative charge is neutralized by the cation of a strong base which, depending on the manner in which the phosphono starting material is prepared, e.g. an alkali metal, e.g. sodium, lithium or potassium ion. The phosphonate starting materials are therefore used as salts in the reaction.

Formula II represents the starting material in the form in which the ring closure takes place. Usually the corresponding phosphoranylidene compound of the formula

Z

H II

Y-c ~ r

1 A 0 - C - R-2

where X! for a trisubstituted, especially a triaryl, e.g. Triphenyl, or a tri lower alkyl, e.g. Trin-n-butyl-phosphoranylidene radical, or the corresponding phosphono compound of the formula

Z

CH-- X2

0 - C - R2

wherein X2 is a phosphono-, especially a dialkyl-phosphono-, e.g. Diethylphosphono is used, wherein a phosphono starting material of formula IIB by treatment with a suitable basic reagent, such as an inorganic base, e.g. an alkali metal carbonate, such as sodium or potassium carbonate, or an organic base, such as a tri-lower alkylamine, e.g. Triethylamine, or an amidine-type cyclic base such as a corresponding diazabicycloalkene compound, e.g. 1,5-diaza-bicyclo [5,4,0] undec-5-ene, in the form suitable for ring closure, i.e. is converted into the compound of formula II.

Preferred starting materials are the phosphoranyl compounds of the formula IIA.

The ring closure can occur spontaneously, i.e. in the manufacture of the starting materials, or by heating, e.g. in a temperature range from about 30 ° C to about 160 ° C, preferably from about 50 ° C to about 100 ° C.

The reaction is preferably carried out in the presence of a suitable inert solvent, such as in an aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. Hexane, cyclohexane, benzene or toluene, a halogenated hydrocarbon, e.g. Methylene chloride, an ether e.g. Diethyl ether, a lower alkylene glycol lower alkyl ether, e.g. Dimethoxyethane or diethylene glycol dimethyl ether, a cyclic ether, e.g. Dioxane or tetrahydrofuran, a carboxamide, e.g. Dimethylform amide, a lower alkyl sulfoxide, e.g. Dimethyl sulfoxide, or a lower alkanol, e.g. Methanol, ethanol or tert-butanol, or in a mixture thereof and, if necessary, in an inert gas, e.g. Argon or nitrogen atmosphere. Optionally, the reaction can be carried out in the presence of an antioxidant such as a sterically hindered phenol, e.g. 2,6-di-tert-butylcresol, or an optionally substituted 1,4-dihydroxybenzene, in particular of hydroquinone.

8th

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

9 646 173

In a compound of the carbonates, alkoxides, phenolates, mercaptides, thiophenolates obtainable according to the invention,

Formula I with an esterified carboxyl group of the formula or amides, e.g. Sodium hydroxide, sodium carbonate, sodium

-C (= 0) -Ra2 can do this in a manner known per se, e.g. trium bicarbonate, sodium ethanolate, sodium thiophenolate,

according to the type of group RA2, into the free carboxyl group via sodium amide or sodium morpholide, or the like. Thus, a suitable 2-halogen- 5 lithium or potassium compound containing water, aqueous lower alkyl, an arylcarbonylmethyl or a 4-nitro or hydroxyl group or also in polar

benzyl group esterified carboxyl group e.g. by using coated solvents with subsequent treatment with a chemical reducing agent, such as sea water. To cleave the 2-cy

tall, e.g. Zinc, or a reducing metal salt such as egg ethoxycarbonyl groups can also be tertiary amines such as a chromium II salt, e.g. Chromium II chloride, usually in io tri-lower alkylamine, e.g. Triethylamine or Hunig base, or the presence of a hydrogen-donating agent which together cyclic or bicyclic amines or imines, such as N-methyl

Men with hydrogen nascent metal to produce morpholine or l, 5-diazabicyclo [5,4,0] undec-5-ene, in one such as an acid, primarily acetic, as well as Ame- inert solvents, such as methylene chloride or tetrahy

sensic acid, or an alcohol, preferably using wasofuran, with the corresponding water being added directly, ammonium salts of the carboxyl compound obtained by an arylcarbonylmethyl group are obtained,

esterified carboxyl group also by treatment with a Si-substituted silylethoxycarbonyl group can be

nucleophilic, preferably salt-forming reagent, such as Na-act with a salt of hydrofluoric acid, the fluo-

trium thiophenolate or sodium iodide, and one provided by ridanions, such as an alkali metal fluoride, e.g. Natri-

4-nitrobenzyl-esterified carboxyl group, also by means of fluorine or potassium fluoride in the presence of a macrocyclic

with an alkali metal e.g. Sodium dithionite, in the 20 see polyether ("crown ether"), or with a fluoride

free carboxyl group can be transferred. An organic quaternary base such as tetraalkylammo-

2-lower alkylsulfonyl-lower alkyl group esterified carboxium fluoride or trialkylarylammonium fluoride, e.g. Tetrahedral

yl group can e.g. by treatment with a basic ethylammonium fluoride or tetrabutylammonium fluoride,

Means, e.g. one of the nucleophilic rea- mentioned below in the presence of an aprotic polar solvent, such as yawing bases, and a carboxyl group esterified into the free grouping by a suitable arylmethyl 25-dimethyl sulfoxide or N, N-dimethylacetamide e.g. be converted by irradiated carboxyl group. A pentachlorophen

len, preferably with ultraviolet light, e.g. below 290 ml | yloxycarbonyl group can be used under mild conditions, e.g.

when the arylmethyl group e.g. one optionally in 3-, 4- by dilute sodium carbonate or sodium bicarbo-

and / or 5-position, e.g. by lower alkoxy and / or ninate solution or by an organic base in the presence of a tro group-substituted benzyl radical, or with long water, converted into a free carboxyl group, wavy ultraviolet light, e.g. over 290 m | i if the

Arylmethyl group e.g. one in 2 position by a nitro one e.g. group substituted by silyl or stannyl groups, substituted benzyl radical, furthermore a carboxyl group can be solvolytically, e.g.

a suitably substituted methyl group such as tert-butyl or by treatment with water or an alcohol is released

Diphenylmethyl, esterified carboxyl group e.g. by becoming 35.

act with a suitable acidic agent, such as ants. If more than one esterified carboxyl group in an er

acid or trifluoroacetic acid, optionally present with the addition of the compound obtainable according to the invention,

a nucleophilic compound, such as phenol or anisole, these can either be converted together or selectively into free esterified carboxyl-carboxyl groups, such as a hydrogenolytically cleavable group.

group, e.g. Benzyloxycarbonyl or 4-nitrobenzyloxycar- 40 In a compound of bonyl obtainable according to the process, by hydrogenolysis, e.g. by treatment with Was- Formula I which contains a free carboxyl group of the formula serstoff in the presence of a noble metal, e.g. Contains Palladiumkata- -C (= 0) -0H, such can be cleaved and released in known lysators. In addition, a manner can be converted to an esterified carboxyl group with a lower alkenyl group, such as with 2-lower alkenyl. by treatment with a suitable special allyl, esterified carboxyl group oxidatively, e.g. 45th diazo compound such as a diazo lower alkane, e.g. Di-by treatment with ozone followed by a reductive azomethane or diazobutane, or a phenyldiazo lowering agent, e.g. Dimethyl sulfide, in a formyl methoxycarbonyl alkane, e.g. Diphenyldiazomethane, if necessary, can be converted into a group from which the carboxyl group is present in the presence of a Lewis acid, e.g. Boron trifluoride, or by treatment with a base such as secondary reaction with an alcohol suitable for esterification in amine, e.g. Dimethylamine, is releasable, or one can use a presence of an esterifying agent such as a carbodi-2-lower alkenyloxycarbonyl group, e.g. Allyloxycarbonyl, imids, e.g. Dicyclohexylcarbodiimide, and carbonyldiimide e.g. by treatment with tristriphenylphosphine rhodium azole, further with an N, N'-disubstituted O- or S-substi-chloride, palladium-on-carbon, or an alkali metal-substituted isourea or isothiourea, in which an O- and lower alkanolate, e.g. Potassium tert-butoxide, in dimethyl sulf S substituent e.g. Lower alkyl, especially tert-butyl,

oxide isomerized to a 1-lower alkenyloxycarbonyl group, 55 phenyl-lower alkyl or cycloalkyl, and N- or N'-substituents and these under weakly acidic or weakly basic ducks e.g. Lower alkyl, especially isopropyl, cycloalkyl hydrolytically cleave conditions. An optionally in or phenyl, or by any other known 2-position substituted by lower alkyl or aryl, 2-oxo and suitable esterification processes such as reaction of an ethoxycarbonyl or 2-cyanoethoxycarbonyl group, e.g. the salt of the acid with a reactive ester of an alko-acetonyloxycarbonyl or 2-cyanoethoxycarbonyl group, 60 hols and a strong inorganic acid, and a strong one under mild conditions, i.e. organic sulfonic acid at room temperature. Furthermore, acid esters (or with cooling), by treatment with a suitable nide, such as chlorides (prepared, for example, by treatment with base in the corresponding salt of this carboxyl group, over-oxalyl chloride), can activate activated esters (formed, for example, with N-hydr) which the free carboxyl group can be obtained by oxy-nitrogen compound, such as N-hydroxy-succinimide) or acid. Suitable bases are nucleophilically mixed anhydrides (obtained, for example, with metal formations which halogenate metal halides, such as alkaline earth metal and in particular alkane lower alkyl esters, such as ethyl chloroformate or chloro limetallate bases, such as corresponding hydroxides, carbonates, isobutylate formate, or with haloacetic acid halo ester).

646 173 10

genides, such as trichloroacetic acid chloride) by reacting with act with formic or trifluoroacetic acid or by hy

Alcohols, optionally in the presence of a base, such as pyrodrogenolysis, an acetonyloxy or cyanoethoxycarbonyl

idin, are converted into an esterified carboxyl group. group by treating with bases such as sodium bicarbonate

In a compound of formula I with an esterified or 1,5-diazabicyclo [5,4,0] undec-5-ene, or a substi-

Grouping of the formula -C (= 0) -RA2 can convert this into a suggested sulfo group by treatment with an alkali metal

whose esterified carboxy group of this formula is converted into halide, if desired stepwise, split off,

e.g. 2-chloroethoxycarbonyl or 2-bromoethoxy- Furthermore, in compounds of the formula I which have a free amino group in carbonyl by treatment with an iodine salt, such as sodium ion or group Rj, this can be done in the presence of a suitable solvent, such as aceto functionally known methods modify. So leaves clay in 2-iodoethoxycarbonyl. io e.g. an amino group by treatment with sulfur

A trioxide represented by an organic silyl or stannyl group, preferably in the form of a complex with an esterified carboxyl group, can be used in a manner known per se, such as an organic base, such as a tri-lower alkylamine, e.g.

be formed, e.g. by converting compounds of formula I, triethylamine, into a sulfoamino group. Furthermore, where R2 is hydroxy, or salts, such as alkali metal, the reaction mixture can be obtained by reaction

e.g. Sodium salts thereof, with a suitable silylating acid addition salt of a 4-guanylsemicarbazide with or stannylating agent, such as one of the abovementioned silyl sodium nitrite, with a compound of the formula I in which R,

Treatment or stannylating agents treated. contains an amino group, and thus react the aminoin

Convert in the process according to the invention, as well as into a 3-guanylureido group.

if or necessary additional measure to be carried out. 2-Penem compounds of the formula I obtained, if necessary, are not involved in the reaction, if necessary, in a manner known per se by oxidation with suitable free functional groups, such as free aminogrup oxidizing agents , such as hydrogen peroxide or peracids, pen eg by acylation, tritylation, or silylation, free e.g. Peracetic acid or 3-chloro-perbenzoic acid, in their hydroxy groups e.g. by etherification or esterification, and 1-oxides can be converted. In this reaction, free carboxyl or sulfo groups e.g. by esterification, care is taken to ensure that, if necessary, free functional incl. silylating groups are temporarily protected in a manner known per se and, if desired, are subsequently protected and, if desired, can be released again after the reaction has taken place .

Salts of compounds of the formula I which are released individually or together in a manner known per se can be in themselves. Thus, known ways existing in a starting material can be produced. Thus one can use salts of amino, hydroxy, mercapto, carboxyl or sulfo groups of such compounds with acidic groups e.g. by e.g. in the form of acylamino such as the above, e.g. Trade in metal compounds such as alkali metal salts of 2,2,2-trichloroethoxycarbonylamino, 2-bromoethoxycarbon suitable carboxylic acids e.g. form the sodium salt of a-ethyl-ylamino-, 4-methoxybenzyloxycarbonylamino- or tert-caproic acid, or with ammonia or a suitable or-butyloxycarbonylamino-, of aryl- or aryl-lower alkyl-ganic amine, preferably stoichiomethioamino-, e.g. 2-nitrophenylthioamino or arylsulfonic amounts or only a small excess of the salt bil ylamino, e.g. 4-Methylphenylsulfonylamino-, used by 1-Niederdendenden means. Acid addition salts of verbin-alkoxycarbonyl-2-propylidene amino groups, or of o-Ni fertilizers of the formula I with basic groupings, give trophenyloxyacetylamino groups or of acyloxy, as can be obtained in a conventional manner, e.g. by treating with an acid the above, e.g. tert-Butyloxycarbonoyloxy, 2,2,2 or a suitable anion exchange reagent. Inner trichloroethoxycarbonyloxy, 2-bromoethoxycarbonyloxy salts of compounds of formula I which e.g. a salt- or p-nitrobenzyloxycarbonyloxy group, or corresponding amino group and acyl mercapto groups that divide a free carboxyl group, or of esterified carb groups, can e.g. by neutralizing salts such as acid oxy such as the above, e.g. Diphenylmethoxycarbonyl, addition salts, to the isoelectric point, e.g. with p-nitrobenzyloxycarbonyl, acetonyloxycarbonyl or weak bases, or by treatment with liquid ion-2-cyanoethyloxycarbonyl groups, or by substituted exchangers. Salts of 1-oxides of Ver-sulfo, such as the above-mentioned lower alkyl sulfo, e.g. Methyl bonds of the formula I with salt-forming groups can be protected by sulfo groups and can be prepared in an analogous manner after the reaction has taken place.

if necessary after conversion of the protective group, salts can be released into the free compounds in a conventional manner. For example, a 2,2,2-trichloroethoxycar can be converted, metal and ammonium salts e.g. by bonylamino or 2-iodoethoxycarbonylamino group or 50 treatment with suitable acids, and acid addition salts, also a p-nitrobenzyloxycarbonylamino group by e.g. by treatment with a suitable basic agent, act with suitable reducing agents, such as zinc in the mixture. Mixtures of isomers obtained can be separated into the individual isomers in the presence of aqueous acetic acid or hydrogen in known methods, in the presence of a palladium catalyst, a Diphenylmethden, mixtures of diastereomeric isomers eg Crystallization by frak-oxycarbonylamino or tert-butylcarbonylamino group 55, adsorption chromatography (co-treatment with formic or trifluoroacetic acid, a column or thin layer chromatography) or other ge-aryl or aryl-lower alkylthioamino group by suitable separation processes. Racemates obtained can usually be treated with a nucleophilic reagent such as sulphurous acid, if necessary after introducing suitable salts of an arylsulfonylamino group by means of electrolytic reforming groups, e.g. by forming a mixture, a 1-Niederalkoxycarbonyl-2-propylidenamino- 60 of diastereoisomeric salts with optically active salt-forming group by treatment with aqueous mineral acid or the agents, separating the mixture into the diastereoisomers of a tert-butyloxycarbonyloxy group by treatment with salts into the free compounds or by fractionated formic or trifluoroacetic acid, or a 2,2,2-trichloro crystallization from optically active solvents, into which anethoxycarbonyloxy group or p-nitrobenzyloxycarbonyl tipodes are separated.

oxy group by treatment with a chemical reduc- 65-

Detergents, such as zinc in the presence of aqueous acetic acid, are preferred those reactions which are carried out under or with hydrogen in the presence of a palladium-neutral, alkaline or weakly basic conditions, or a diphenylmethoxycarbonyl group by loading.

The process also includes those embodiments according to which compounds obtained as intermediates are used as starting materials and the remaining process steps are carried out with them, or the process is terminated at any stage; furthermore, starting materials in the form of derivatives can be used or formed in situ, if appropriate under the reaction conditions. For example, a starting material of formula II, wherein Z is oxygen, from a compound of

1 646173

Formula II, in which Z 'is an optionally substituted methylidene group, can be prepared in situ by ozonization and subsequent reduction of the ozonide formed, analogously to the process given in step 2.5, whereupon, in particular if R) is hydrogen, in the reaction solution is cyclized to the compound of formula I.

The starting materials of formula II or IIA or IIB used according to the invention can e.g. according to the following reaction scheme:

Reaction scheme 1

0

H

.O-acyl

• NH

Level 1.1)

0

z '

H II Ls - e - ri

• NH

iii

IV

VI

\ l /

H

Level 1.4

Z '

II

S - C - Rn

0

N

\ c © _ x®

o = c - r;

v

Level 2

0

H II

s - c - r,

- N \

CH X,

I A 0 - C - Ro

4-

Level 1.3

0

H II • S - C - R,

- N \

CH OH I a

0 - C - RV "

II

646 173 12

In the compounds of formulas IV, V, VI and II mixed with a base, e.g. an alkali metal hydroxide, such as

Reaction Scheme I and sodium hydroxide in the compounds of the formulas.

Xa, XI, XII and IVa in Reaction Scheme 2 is Z 'oxygen, stage 1.2: an a-hydroxycarboxylic acid compound of sulfur or, especially when R 1 is hydrogen, formula V is obtained by using a compound of one optionally by one or two substituents Y: Formula IV with a glyoxylic acid compound of the formula substituted methylidene group which can be converted by oxidation into an OHC-C (= 0) -RA2 or a suitable derivative, such as an oxo group Z. A substituent Y hydrate, hemihydrate or hemiacetal, e.g. a hemiacetal of this methylidene group is an organic radical, e.g. with a lower alkanol, e.g. Methanol or ethanol, or one of the organic radicals mentioned under Rt, as is used, if desired, separating an isomer mixture obtained into those of the optionally substituted lower alkyl or individual isomers, if desired in an cycloalkyl, cycloalkyl lower alkyl or phenyl or phenyl riveted compound a group R! into another group R [deralkylreste, and in particular one of the functionally converted, and / or, if desired, an optionally deleted, such as esterified, including with an optically active substituted methylidene group Z 'into an oxo group Z alcohol, such as 1-menthol, esterified carboxyl groups . This convicted.

Methylidene group preferably bears one of the above-mentioned compounds. The compound V is usually obtained as a mixture of substituents. The 2-carbomethoxymeth- of the two isomers should be emphasized (with regard to the ylidene group and the 2-carbo-l-menthyloxymethylidene group Z '. PaCH <^ OH). However, the pure isomers can also be

The latter can isolate from to produce optically active connections.

of the formulas IV to VI and II can be used. The attachment of the glyoxylic acid ester compound to the

Step 1.1: A thio-azetidinone of formula IV is obtained. The nitrogen atom of the lactam ring is found at room temperature by adding an acyloxyazetidinone of formula III with or, if necessary, with heating, e.g. up to about 100 ° C,

ner mercapto compound R] -C (= Z ') - SH or a salt, in the absence of an actual condensation

e.g. an alkali metal such as sodium salt thereof treated by means of and / or without the formation of a salt. When using

if desired, a mixture of isomers obtained in the formation of the hydrate of the glyoxylic acid compound, water is separated from individual isomers, if desired formed in a obtained mixture which, if necessary, by distillation, e.g. azeo-

a group Rj into another group R] trop, or by using a suitable dehydrated

transferred, and / or, if desired, a given substitution agent, such as a molecular sieve, is removed. In front-

tuated methylidene group Z 'converted into an oxo group Z. preferably one works in the presence of a suitable

Acyloxy-azetidinones of the formula III are known (interpreting agents, such as, for example, dioxane, toluene or dimethylformic laid-open publication 1 906 401) or can be prepared by the be-30 amide, or solvent mixture, if desired or known methods. The acyl residue may have the same meaning in the atmosphere of an inert gas as the acyl residue Rj-CO-, the acyl nitrogen.

rest can also be derived from an optically active acid. An optically inactive (4R, S) -

A preferred acyl group is acetyl. Compound of formula IV as well as a corresponding op-

This nucleophilic substitution can be used under neutral or table active (4R) or (4S) compounds,

weakly basic conditions in the presence of water A racemate of the formula V obtained can be converted into the optically

and optionally a water-miscible organic compound.

see solvents are carried out. The basic loading stage 1.3: Compounds of the formula VI in which XQ represents a condition can be prepared, for example, by adding an inorganic reactive hydroxy group, in particular a niche base, such as an alkali metal or alkaline earth metal, halogen or organic sulfonyloxy.

hydroxides, carbonates or bicarbonates, e.g. of, by in a compound of formula V the

Sodium, potassium or calcium hydroxide, carbonate or secondary hydroxy group in a reactive esterified

-hydrogen carbonate. As an organic Lö-hydroxy group, especially in halogen, e.g. Chlorine or solvents can e.g. water-miscible alcohols, e.g. Bromine, or into an organic sulfonyloxy group, such as

Lower alkanols such as methanol or ethanol, ketones, e.g. 45 lower alkylsulfonyloxy, e.g. Methylsulfonyloxy, or

Lower alkanons such as acetone, amides, e.g. Lower alkancar arylsulfonyloxy, e.g. 4-methylphenylsulfonyloxy, converted

bonsamic acid amides, such as dimethylformamide, and the like, if desired, an isomer mixture obtained is used in the. The reaction is usually separated in the case of spatial isomers, if desired in a

temperature carried out, but can also be carried out in an elevated or low compound, a group R] in another group R i lower temperature. transferred, and / or, if desired, an optionally

In the reaction both an optically inactive (4R, S) - substituted methylidene group Z 'into an oxo group Z

Compound of formula III, as well as a corresponding op-transferred.

table active (4R) or (4S) connection. The compound VI can be in the form of mixtures

A racemate of the formula IV obtained can be separated into the optically the isomers (with respect to the grouping> CH tw X0) or active compounds. The racemic ver is obtained in the form of pure isomers.

Binding of formula IV, wherein R is methyl and Z 'oxygen. The above reaction is indicated by treatment with an is known (esterification agent suitable for K. Clauss et al., Liebigs Ann. Chem., for example by using 1974, 539 560). a halogenating agent such as a thionyl halide, e.g.

fio -chloride, a phosphorus oxyhalide, especially -chloride, or a mercapto compound Ri ~ C (= Z ') - SH, in which Z' is a halophosphonium halide, such as triphenylphos, optionally substituted by one or two substituents Y, or substiindine dibromide or iodide, and a suitable organic tuated methylidene group or a salt thereof, sulfonic acid halide, such as chloride, can preferably be prepared in situ, if appropriate, by exposing a basic, primarily organic, basic-speaking isothiuronium salt of the formula 65 such as an aliphatic tertiary amine, e.g. R] -C (= Z ') - S-C (NH2) (= NH2®). A® where A® is an anion, triethylamine, diisopropylethylamine or «polystyrene-Hü-e.g. the chloride anion means in water, an alcohol, nig base, or a heterocyclic base of the pyridine type, such as methanol or ethanol, or a water-alcohol mixture e.g. Pyridine or collidine. Preferably works

13 646173

in the presence of a suitable solvent, e.g. Become. A racemate of the formula II obtained can be separated into the oxane or tetrahydrofuran, or a solvent-optically active compound.

if necessary, with cooling and / or in the atmosphere. The cleavage of the aforementioned racemates into their sphere of an inert gas, such as nitrogen. Optical antipodes are carried out according to known Me in a compound of formula VI so obtainable 5 thoden.

a reactive esterified hydroxyl group X0 into one - one of these methods consists in allowing a race-reactive esterified hydroxyl group to be reacted with an optically active auxiliary, which is known to be converted. So you can e.g. a resulting mixture of two diastereomeric connective chlorine atoms is separated by treating the appropriate chlorine fertilizers with the aid of suitable physico-chemical bonding with a suitable bromine or iodine reagent, in particular methods, and the individual diastereomeric compounds, in particular with an inorganic bromide or iodide salt , then fertilize in the optically active starting materials such as lithium bromide, preferably in the presence of a suitable cleaved.

solvent, such as ether, by means of a bromine or iodine.

replace atom. mates are those that have an acidic group, e.g. the

Both an optically inactive (4R, S) -15 racemate of the compound of the formula I and others of the described compound of the formula V as well as a corresponding open racemate can be introduced into the reaction by simple reactions in table-active (4R) - or (4S) connection can be used. convert acidic racemates. For example, Alde-A obtained racemate of the formula VI can be separated into the racemates bearing optically hyde or keto groups with an acidic active compound. Group bearing hydrazine derivative, e.g. 4- (4-carboxy

Step 1.4: A starting material of the formula II is obtained-20 phenyl) -semicarbazide to the corresponding hydrazone, by a compound of the formula VI, in which X0 is vaten or alcohol-containing compounds having a reactive esterified hydroxyl group Dicarboxylic anhydride, e.g. Phthalic anhydride, a suitable phosphine compound, such as a tri-lower to the racemate of an acidic half-ester.

alkylphosphine, e.g. Tri-n-butyl-phosphine, or a triar- These acidic racemates can be mixed with optically active Ba-

yl-phosphine, e.g. Triphenylphosphine, or with a suitable one, e.g. Esters of optically active amino acids, or (-) - th phosphite compound, such as a tri-lower alkyl phosphite, brucine, (+) - quinidine, (-) - quinine, (+) cinquinone, (+) - De-e.g. Triethyl phosphite, or an alkali metal dimethohydabietylamine, (+) - and (-) - ephedrine, (+) - and (-) - 1-

treated with ylphosphite, or by treating a compound of phenylethylamine or its N-mono- or dialkylated formula V with a carbon tetrachloride and a Phos derivative to form mixtures consisting of two diastereoisomers, with 30 salts depending on the choice of the reagent , are implemented.

Compound of formula IIA or IIB can be obtained- in carboxyl-containing racemates, e.g. if desired, in a compound obtained a group in racemates which converts a functionally modified carboxy-R] into another group R, and / or contain desired methylidene group Z ', this carboxyl group can optionally replace an optionally substituted methylidene group Z' by an optically active alcohol, such as (-) -Menthol, (+) converted into an oxo group Z. 35-borneol, (+) - or (-) - 2-octanol are or will be esterified,

The reaction starting from the compound of formula VI, after isolation of the desired diastereo ion, is preferably carried out in the presence of a suitable inert mer, the carboxyl group is released, or the solvent, such as a hydrocarbon, e.g. Hexane, esterified part of the molecule containing carboxyl group, e.g. the ver-cyclohexane, benzene, toluene or xylene, or an ether, esterified carboxymethylidene, is split off.

e.g. Racemates containing dioxane, tetrahydrofuran or diethylene glycol dimeth 40 hydroxyl groups can also be carried out with ether or a solvent mixture. Depending on their optical antipodes are split, in particular according to reactivity one works with cooling or with special optically active acids or their reactive, elevated temperature, for example between -10 ° and + 200 °, functional derivatives which are used with the preferably at about 20 ° to 180 °, and / or in the atmosphere known as alcohols form diastereomeric esters. Such inert gas gases as nitrogen. To prevent oxidation, for example, (-) - Abietic acid, D (+) - and L (-) -ver processes can contain catalytic amounts of an antioxidant, malic acid, N-acylated optically active amino acids, (+) - e.g. p-hydroquinone can be added. and (-) - camphanic acid, (+) - and (-) - ketopic acid, L (+) -

The use of a phosphine-ascorbic acid, (+) - camphoric acid, (+) - camphor-10-sulfone compound is usually carried out in the presence of a basic mitic acid (ß), (+) - or (-) - a-bromocampher- rc-sulfonic acid,

means such as an organic base, e.g. an amine, such as triethyl D (-) quinic acid, D (-) - isoascorbic acid, D (-) - and L (+) - ylamine, diisopropylethylamine or "polystyrene-Hunig-mandelic acid, (+) - 1 -Mentoxyacetic acid, D (-) - and L (+) -base », and thus arrives directly at the phosphoranylidene-tartaric acid and its di-O-benzoyl and di-op-toluylderi starting material of the formula IIA, which is derived from the corresponding father. The acyl residues of the optically active acids mentioned phosphonium salt is formed. j5 can be used, for example, as acyl in compounds of the formula

III or as R] -C (= O) - in compounds of the formulas II and Re-IV to VI starting from a compound of the formula V and the racemate resolution of such a compound action will be possible in a solvent under mild conditions. If desired or necessary, gen. at temperatures from -10 ° to about 40 °, preferably after the racemate resolution, the optically active group at room temperature. The solvent used is o, C (= O) - in particular an excess of carbon tetrachloride, the Ri ~ C (= O,) - is converted into a desired optically inactive group.

additional methylene chloride can be added. Racemates containing Phos hydroxyl groups can be converted into a phine, the above-mentioned tri-lower alkyl or triaryl mixture of diastereomeric urethanes, suitable for phosphines, in particular triphenylphosphine, for example by reaction with optically active isocyanates, two equivalents of which are used. 65 th, as with (+) - or (-) - 1-phenylethyl isocyanate.

In the reaction, both an optically inactive (4R, S) basic racemate can form a compound of the formula VI or V as well as a corresponding diastereomeric salt with the abovementioned acids. Racemates containing, for example, double bonds containing optically active (4R) or (4S) compound can be used with platinum chloride and

646 173

14

(+) - l-Phenyl-2-aminopropane are converted into mixtures of diastereomeric complex salts.

Physico-chemical methods are suitable for separating the diastereomer mixtures, primarily fractional crystallization. However, chromatographic methods can also be used, especially solid-liquid chromatography. Volatile diastereomer mixtures can also be separated by distillation or gas chromatography.

The separated diastereomers are also cleaved into the optically active starting materials by customary methods. The acids or bases are liberated from the salts, e.g. by treatment with stronger acids or bases than those originally used. The desired optically active compounds are obtained from the esters and urethanes, for example after alkaline hydrolysis or after reduction with a complex hydride, such as lithium aluminum hydride.

Another method for separating the racemates consists in chromatography on optically active absorption layers, for example on cane sugar.

According to a third method, the racemates are dissolved in optically active solvents and the less soluble optical antipode is crystallized out.

A fourth method uses the different reactivity of the optical antipodes against biological material such as microorganisms or isolated io enzymes.

According to a fifth method, the racemates are dissolved and one of the optical antipodes is crystallized by inoculation with a small amount of an optically active product obtained by the above methods.

15

Optically active trans compounds of the formula IVa which can be used according to the invention can also be prepared according to the following reaction scheme:

Reaction scheme 2

H S

Level 2.1

0 = 1

Level 2.2

H S-S-Rc

H

S-S-R

O

0

■ N CH "

xc = c

\

CH,

OC-R,

(X)

Level 2.3 4

o = J

■ n ch9

\ # 2

ch - c

0 = C-R ^ CH3

(XX)

Level 2.4

Level 2.4a

15

646173

(XI)

H

Z '

left

S-C-R

1

Level 2.3;

0

N

(Xa)

CH - C I a \

0 = C-R ^ CH 2 J

Level 2.5

Z '

II

H S-C-R,

Level 2.6

0 == "

NH

(XII) 0 = C -RJ

In the compounds of the formulas VII to XII, RA2 preferably denotes lower alkoxy, in particular methoxy.

Step 2.1: An oxide of a penicillinic acid compound of the formula VIII is obtained by oxidizing a penicillanic acid compound of the formula VII in the 1-position. The oxidation is carried out in a manner known per se using suitable oxidizing agents, such as hydrogen peroxide or inorganic or organic peracids. Suitable inorganic peracids are e.g. Periodic or persulfuric acid. Suitable organic peracids are e.g. Percarboxylic acids such as performic acid, peracetic acid, trifluoroperacetic acid, permaleic acid, perbenzoic acid, 3-chloro-perbenzoic acid or monoperphthalic acid, or persulfonic acids, e.g. p-toluenesulfonic acid. The peracids can also be prepared in situ from hydrogen peroxide and the corresponding acids. The oxidation takes place under mild conditions, e.g. at temperatures from about -50 ° to about + 100 °, preferably at about -10 ° to about + 40 °, in an inert solvent.

Starting compounds of the formula VII are known or can be prepared analogously to known processes. For example, they can be hydrogenated by potassium 6a-bromo-penicillanic acid and subsequent esterification of the carboxyl group [E. Evrard, M. Claesen and H. Vanderhae-ge, Nature 201 1124 (1964)] or by hydrogenation of 6,6-dibromophenicillanic acid esters, e.g. the methyl ester [J.P. Clayton, J. Chem. Soc. (C), 2123 (1969)].

45

55

60

(IVa)

Step 2.2: A 3-methylene butyric acid compound of the formula IX is obtained by treating a 1-oxide of a penicil-lanoic acid compound of the formula VIII with a mercapto compound R ° -SH.

In the mercapto compound R ° -SH and in the reaction product of the formula IX, R ° is an optionally substituted aromatic heterocyclic radical having up to 15, preferably up to 9 carbon atoms, and at least one ring nitrogen atom and optionally another ring heteroatom, such as oxygen or sulfur, which The rest of one of its ring carbon atoms, which is connected to a ring nitrogen atom by a double bond, is bonded to the thio group -S-. Such radicals are monocyclic or bicyclic and can be substituted, for example, by lower alkyl, such as methyl or ethyl, lower alkoxy, such as methoxy or ethoxy, halogen, such as fluorine or chlorine, or aryl, such as phenyl.

Such residues R ° are e.g. monocyclic five-membered thiadiazacyclic, thiatriazacyclic, oxadiazacyclic or oxatriazacyclic residues of aromatic character, in particular, however, monocyclic five-membered diazacyclic, oxazacyclic and thiazacyclic residues of aromatic character, and / or primarily the corresponding benzdi-azacacyclic, benzox-azacyclic, benzox-azacyclic, benzox is

646 173 16

and has an aromatic character, in which R 4 is a 4-mercaptoazetidine

substitutable ring nitrogen atom e.g. by lower alkyl 2-ones to the triple bond of the alkyne can be spontaneously substituted at. Representative for such groups R ° of the reduction temperature.

are l-methyl-imidazol-2-yl, 1,3-thiazol-2-yl, 1,3,4-thiadi stage 2.3a: a thio compound of the formula XI becomes azol-2-yl, 1,3,4,5 -Thiatriazol-2-yl, 1,3-oxazol-2-yl, 5 also obtained by using a compound of formula Xa

1,3,4-oxadiazol-2-yl, 1,3,4,5-oxatriazol-2-yl, 2-quinolyl, according to the reaction conditions of step 2.3 by loading

1-methyl-benzimidazol-2-yl, benzoxazol-2-yl and in particular are isomerized with a suitable basic agent,

their benzthiazol-2-yl. and, if desired, in a compound obtained

The reaction is converted into an inert solvent, such as a group Rj into another group R, and / or an aliphatic or aromatic hydrocarbon, if desired an optionally substituted methyl

e.g. Benzene or toluene, converted to an oxo group Z while heating to the reflux group Z '.

temperato of the solvent used. Step 2.4a: A compound of the formula Xa is obtained

Step 2.3: A 3-methylcrotonic acid compound of the forms by obtaining a 3-methylenebutyric acid compound of mei X is obtained by using a methylenebutyric acid formula IX according to the reaction conditions of step 2.4

Compound of formula IX treated with a suitable 15 treated with a suitable reducing agent and

Neten basic agent isomerized. early or later with an acylation derivative

Suitable basic agents are, for example, organic carboxylic acid of the formula Rp-C (= Z) -OH, or, if Z 'is a nitrogen base, such as tertiary amines, e.g. Tri-lower alkylamido, optionally substituted by Y-substituted methylidene, such as triethylamine or Hunig base, or also inorganic, with an alkyne of the formula R, -C s CY, see bases which are in an inert solvent, such as a 20 and if desired in a compound obtained a possibly halogenated hydrocarbon, for example Meth group R | to another group R! converted, and / or ylene chloride, converted to an oxo group Z at room temperature or, if desired, an optionally substituted methyl reduced or elevated temperature, if desired.

long. Step 2.5: A 2-oxoacetic acid compound of the formula Step 2.4: A thio compound of the formula XI is obtained -25 XII is obtained by ozonizing a compound of the formula by a compound of the formula X with a GE-XI and the ozonide formed treated reductively to the oxo-suitable reducing agent and cleaved at the same time or group, and, if desired, converted an Rj group into another R, group, of the formula R] -C (= Z) -OH, or in an obtained reaction with an acylation derivative of a carboxylic acid bond , if Z 'represents a optionally and / or if desired an optionally substituted methylidene group substituted by Y, with ei-30 methylidene group Z' converted into an oxo group Z, reacting an alkyne of the formula Rj-C s CY, and desired die Ozonization is usually carried out with an ozone group, if at all, in a compound obtained! in oxygen mixture in an inert solvent, such as converting another group Ri, and / or desired lower alkanol, e.g. Methanol or ethanol, if an optionally substituted methylidene group Z 'in lower alkanone, e.g. Acetone, an optionally halogen-an oxo group Z transferred. 35 renal aliphatic, cycloaliphatic or aromatic

Suitable reducing agents are, for example, hydride hydrocarbon, e.g. a halogen lower alkane such as reducing agents such as alkali metal borohydrides e.g. Sodium methylene chloride or carbon tetrachloride, or in a borohydride, or also zinc in the presence of a carboxylic acid, solvent mixture, including an aqueous mixture,

e.g. a carboxylic acid of the formula R] -C (= Z) -OH. The preferably under cooling, e.g. at temperatures of around -90 °

Hydride reducing agents are usually carried out in the presence of 40 to about 0 °.

of suitable solvents, such as dimethylformamide. An intermediate ozonide is usually

used. The hydride reduction is preferred in dimethyl, without being isolated, reductively to a compound

cleaved formamide with sodium borohydride at temperatures of about manure of the formula XII, with catalytically active

-50 ° to -10 °, preferably at about -20 °, whereupon fourth hydrogen, e.g. Hydrogen is added in the presence of an acylating agent at the same temperature and against a heavy metal hydrogenation catalyst, such as a nickel, and furthermore a tertiary base, such as pyridine. The palladium catalyst, preferably on a suitable one

Reduction with zinc and a carboxylic acid is given - carrier material, such as calcium carbonate or carbon, or chemical

if in a solvent, for which the carboxylic acid, if they mix reducing agents, such as reducing heavy metals,

is liquid, can serve itself, at temperatures of around -10 including heavy metal alloys or amalgams, e.g. Zinc, in up to about + 50 ° preferably at about 0 ° to room temperature 50 presence of a hydrogen donor such as an acid e.g.

carried out. The acylating agent can be reducing acetic acid, or an alcohol, e.g. Lower alkanol,

mixture can be added from the beginning or after finishing decorative inorganic salts such as alkali metal iodides, e.g.

reduction and optionally after evaporation sodium iodide or alkali metal bisulfites, e.g. Natri-

the carboxylic acid used and / or the solvent. umhydrogen sulfite, in the presence of a hydrogen donor,

Suitable acylating agents are in particular the anhydrides such as an acid, e.g. Acetic acid, or water, or reduced

of the carboxylic acids mentioned, such as symmetrical anhydrides, or organic compounds, such as formic acid,

e.g. Acetic anhydride, or mixed anhydrides, preferably det. As reducing agents there are also compounds with hydrohalic acids, i.e. the corresponding insert, which is easily incorporated into corresponding epoxy compounds or the carboxylic acid halides, e.g. the chlorides and bromides, oxides can be converted, the epoxy

like acetyl bromide. For example, a compound of the dung due to a C, C double bond and the oxide formation

- Formula X with zinc in a mixture of acetic acid and manure due to the presence of an oxide-forming hetero-,

Acetic anhydride can be carried out at 0 ° to about 20 ° in a compound of the form such as sulfur, phosphorus or nitrogen atom,

Mei XI are transferred, wherein Rj is methyl. Because of such connections e.g. suitable substituted ethene

The zinc / carboxylic acid compounds (which are used in the reaction in ethylene

re-reduction preferred. The alkyne can also be converted from anges), such as tetracyanoethylene,

begin or only after completion of the reduction to the particularly suitable sulfide compounds (which in the reaction in

Reducing solution are added. The addition of those to be converted in sulfoxide compounds), such as diene

17 646173

alkyl sulfides, primarily dimethyl sulfide, suitable organisose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or see phosphorus compounds such as a phosphine, the added or glycine, and lubricants, e.g. Silica, talc, optionally substituted aliphatic or aromatic carboxylic acid or salts thereof, such as magnesium or calcium hydrogen radicals as substituents (and which can have stearate and / or polyethylene glycol; tablets of the reaction are converted into a phosphine oxide) ), like s also contain binders, e.g. Magnesium aluminum tri lower alkyl phosphines, e.g. Tri-n-butylphosphine, or silicate, starches such as corn, wheat, rice or arrowroot triarylphosphines, e.g. Triphenylphosphine, also phosphites, starch, gelatin, tragacanth, methyl cellulose, sodium carb- which optionally substituted aliphatic hydrocarbon oxymethyl cellulose and / or polyvinylpyrrolidone, and, if they contain residues of substituents (and are desired in the reaction) and disintegrants, for example starches, agar, alginic acid or be converted into phosphoric acid triesters) such as tri-lowers -> a salt thereof, such as sodium alginate, and / or Brausemi-alkyl-phosphites, usually in the form of corresponding compounds, or adsorbents, colorants, flavor-the alcohol adduct compounds, such as trimethylphosphite, substances and In addition, the new pharmaco-or phosphorous acid triamides, which optionally have compounds which have a substance-effective action in the form of injectable, tuitioned aliphatic hydrocarbon radicals as substituents, for example intravenously administrable preparations or of infusion, such as hexane-lower alkyl-phosphorous acid triamides, can be used in 15 ion solutions the. Such solutions are preferred e.g. Hexamethylphosphoric acid triamide, the latter preferably isotonic aqueous solutions or suspensions, sometimes in the form of a methanol adduct, further suitable for these e.g. from lyophilized preparations which convert the active nitrogen bases (which are converted into the corresponding N substance in the reaction alone or together with a carrier material, oxides), such as heterocyclic nitrogen e.g. Mannitol, can be prepared before use with an aromatic character, e.g. Bases of pyridine type 20 nen. The pharmaceutical preparations can be sterilized and in particular pyridine itself. The cleavage of the usual and / or auxiliary substances, e.g. Preservation, stabilization, wetting of non-isolated ozonide is normally carried out under and / or emulsifiers, solubilizers, salts for the conditions used for its production, regulation of the osmotic pressure and / or buffers, i.e. in the presence of a suitable solvent or solvent. The present pharmaceutical preparations, which, mixed with a mixture of solvents, and, if desired, heat further pharmacologically valuable substances with cooling or light heating, preferably at temperatures of from, are prepared in a manner known per se, e.g. approx. -10 ° C to approx. + 25 ° C and the reaction is usually completed by conventional mixing, granulating, coating, punching at room temperature. solution or lyophilization processes.

Step 2.6: A compound of the formula IVa is obtained, from about 0.1% to 100%, in particular from about 1%, by solvolysing a compound of the formula XII, and 30 about 50%, lyophilisates up to 100% of the Active ingredient.

if desired, in a compound obtained, a group in connection with the present description

Rt is converted into another group R, and / or, if desired, contains organic radicals designated “lower”, unless an optionally substituted methylidene group is not expressly defined, up to 7, preferably up to 4

T converted into an oxo group Z. Carbon atoms; Acyl residues contain up to 20, preferably

Solvolysis can be carried out as hydrolysis, or preferably as 35, up to 12 and primarily up to 7 carbon atoms.

Alcoholysis are carried out, usually using atoms.

with a lower alkanol, e.g. Methanol or ethanol, um- The following examples serve to illustrate the inventions

puts. The alcoholysis is preferably carried out in the presence of manure; Temperatures are given in degrees Celsius.

Water and an organic solvent, such as the following abbreviation is used: DC = thin-layer

Lower alkyl carboxylic acid lower alkyl esters, e.g. Acetic acid 40 matogram on silica gel.

ethyl ester, preferably at room temperature, if necessary carried out with cooling or heating. The a-keta-example 1 carboxylic acid of formula XIII does not necessarily need (4 R, S) -4-acetylthio-2-oxo-azetidine.

to be isolated. Do you e.g. the cleavage of the ozonide A solution of 138 mg (1.07 mM) (4 R, S) -4-acetoxy-in the presence of a solvolysis agent, e.g. Water, by, 45 azetidin-2-one in 0.4 ml of water and 0.1 ml of acetone is obtained directly at room temperature so that a compound of formula IVa can be added dropwise with a solution of 0.12 ml. Thioacetic acid in 1.6 ml IN sodium hydroxide solution added In compounds IV to XII, II and IVa one and at the same temperature can be stirred overnight. The ReGroup R or RA2 in known manner in an action mixture will exhaustively be converted with another group R or RA2 with methylene chloride, whereby 50 is traced. The combined organic phases can be used using the same methods as drying sodium sulfate and evaporating in vacuo. The residue to convert these substituents in the compounds is on silica gel with toluene-ethyl acetate 4: 1 until the formula I is given. 3: 2 chromatographed and gives the title compound with

Compounds IV to VI and II can have the following physicochemical properties. TLC: Rf = optionally substituted methylidene group Z 'by ozonization 55 0.29 (toluene-ethyl acetate 2: 3); IR spectrum (CH2CI2): separation and subsequent reduction of the ozonide formed, sorption bands at 2.95; 5.6; 5.9; 8.85 | i.

according to the procedure described in step 2.5, into a

Oxo group Z are transferred. Example 2

The pharmacologically usable compounds of 2 - [(4 R, S) -4-acetylthio-2-oxo-l-azetidinylJ-2-hydroxyes-

present invention can e.g. for the production of 60 p-nitrobenzyl acetate.

pharmaceutical preparations are used, which are at room temperature 3.3 g (22.75 mM) (4 R, S) -4-effective amount of the active substance together or in the acetylthio-2oxo-azetidine with a solution of 12.9 g 2-ethical mixture with inorganic or organic, solid or liquid oxy-2-hydroxy-acetic acid p-nitrobenzyl ester in a mixture containing pharmaceutically usable excipients, 240 ml of toluene and 60 ml of dimethylformamide, which are added enteral or parenteral administration. 65 After adding freshly dried molecular sieves, tablets or gelatin capsules are used which contain the mixture under nitrogen overnight at room temperature together with the active ingredient together with diluents, e.g. Lacquer and then stirred at 50 ° for 2 hours. The

646173

18th

Molecular sieves are filtered off, washed with toluene and the filtrate and washing liquid are evaporated together in vacuo. The residue is dried under high vacuum and chromatographed on silica gel with toluene-ethyl acetate 9: 1. After elution of unreacted p-nitrobenzyl 2-ethoxy-2hydr-oxyacetic acid, the title compound is eluted with the following physicochemical properties: TLC: Rf = 0.31 (toluene-ethyl acetate 2: 3); IR spectrum (CH2C12): absorption bands at 2.8; 5.6; 5.7; 5.87; 6.55 and 7.4 n

Example 3

2-f (4 R, S) -4-acetylthio-2-oxo-l-azetidinyl] -2-triphenyl-phosphoranylidene-acetic acid-p-nitrobenzyl ester.

a) A solution of 2 g of 2 - [(4 R, S) -4-acetylthio-2-oxo-l-azetidinyl] -2-hydroxyacetic acid p-nitrobenzyl ester in 40 ml of absolute dioxane becomes a solution which has been stirred for 30 minutes of 5.5 g of poly Hunig base in 20 ml of absolute dioxane. After adding a solution of 1.87 ml (3.5 equivalents) of thionyl chloride in 30 ml of absolute dioxane, the reaction mixture is stirred for 5 hours at room temperature and under nitrogen. The poly-Hunig base is filtered off and the filtrate is evaporated in vacuo.

b) The crude 2 - [(4 R, S) -4-acetylthio-2-oxo-l-azetidinyl] -2-chloroacetic acid p-nitrobenzyl ester obtained is dissolved in 107 ml of absolute dioxane, with 7 g of poly-Hunig base and 2.85 triphenylphosphine added and stirred for 15 hours at 50 ° under nitrogen. The poly-Hunig base is filtered off, washed with dioxane and the filtrate and washing liquid are evaporated together in vacuo. The residue is chromatographed on silica gel with toluene-ethyl acetate and gives the title compound with the following physicochemical properties: TLC: Rf = 0.24 (toluene-ethyl acetate 2: 3); IR spectrum (CH2C12): absorption bands at 5.67; 5.9; 6.15; 6.55; 7.42; 9.05 and 9.25 | i.

c) The same title compound can also be obtained by using 0.44 mM 2 - [(4R, S) -4-acetylthio-2-oxo-l-azetidinyl] -2-hydroxyacetic acid p-nitrobenzyl ester in a mixture of 2 ml of methylene chloride and 0.2 ml of carbon tetrachloride with 1 mM triphenylphosphine stirred for 4 hours at room temperature and 30 minutes at 40 ° C, the reaction mixture diluted with methylene chloride, washed with aqueous sodium bicarbonate solution, dried over sodium sulfate, evaporated in vacuo and the residue with silica gel with Chromatographed toluene-ethyl acetate 2: 3.

Example 4

(5 R, S) -2-methyl-2-penem-3-carboxylic acid p-nitrobenzyl ester.

A solution of 100 mg (0.167 mM) of 2 - [(4 R, S) -4-acetyl-thio-2-oxo-1-azetidinyl] -2-triphenylphosphoranylidene acetic acid p-nitrobenzyl ester in 50 ml of absolute toluene is added added a catalytic amount of hydroquinone and stirred under nitrogen overnight at 90 °. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel with toluene-ethyl acetate 19: 1. The title compound is obtained in the form of yellowish crystals with the following physicochemical properties: mp 130-132 °; E> C: Rf = 0.54 (toluene ethyl acetate 2: 3); UV spectrum (ethanol): A, max = 308 nm (e = 10 036); 262 nm (s = 13 090); Ir spectrum (CH2C12): absorption bands at 5.57; 5.82; 6.3; 6.55; 7.4; 7.6 and 8.3 n; NMR spectrum (in CDC13 / 100 Mc; in ppm): 8.25 = 2H, m; 7.65 = 2 H, m; 5.65 = 1H, q; 5.35 = 2H, m; 3.4-3.9 = 2H, m; 2.4 = 3 H, s.

Example 5

(5 R, S) -2-methyl-2-penem-3-carboxylic acid.

i) A solution of 50 mg (5 R, S) -2-methyl-2-penem-3-carboxylic acid p-nitrobenzyl ester in 3 ml of absolute ethyl acetate-

5 tat is mixed with 2 ml of 0.2 M aqueous sodium hydrogen carbonate solution and 100 mg of 10% palladium / carbon catalyst and stirred under normal pressure for 35 minutes under hydrogen. The hydrogenation mixture is filtered off from the catalyst via diatomaceous earth, washed with 0.7 ml of 0.2 M sodium bicarbonate solution and ethyl acetate, and the filtrate and washing liquid are freed from the ethyl acetate in vacuo. The remaining aqueous solution is acidified with 5 ml of 5% aqueous citric acid solution and extracted exhaustively with methylene chloride. The combined organic phases are dried over sodium sulfate, filtered, evaporated in vacuo and dried in a high vacuum. The title compound obtained has the following physicochemical properties: IR spectrum (CH2C12): absorption bands at 5.57 and 5.95 | i; Nuclear Magnetic Resonance Spectrum 20 (DMSO d6 / 100 Mc; in ppm): 5.65 = 1H, q; 3.3-3.9 = 2H, m (+ H20); 2.28 = 3H, s.

ii) A solution of 700 mg (2.18 mM) (5 R, S) -2-methyl-2-penem-3-carboxylic acid p-nitrobenzyl ester in 42 ml of absolute

25 ml of ethyl acetate are mixed with 28 ml of 0.2 M aqueous sodium hydrogen carbonate solution and 1 g of 10% palladium / carbon catalyst and stirred under normal pressure for 90 minutes under hydrogen. The hydrogenation mixture is filtered off from the catalyst via diatomaceous earth, washed with 0.2 M 30 sodium hydrogen carbonate solution and ethyl acetate and the filtrate and washing liquid are combined. The aqueous phase is separated off, washed with methylene chloride, acidified with 5 ml of 5% aqueous citric acid solution and extracted exhaustively with methylene chloride. The 35 combined organic phases are dried over sodium sulfate, filtered, evaporated in vacuo and dried in a high vacuum. The title compound obtained is crystallized from diethyl ether acetone and has the following physicochemical properties: Melting point: 140-167 ° (un-40 sharp, decomposition); TLC: Rf = 0.17 (toluene-ethyl acetate 3: 2 + 5% acetic acid), IR spectrum (KBr): absorption bands at 3.4; 3.6; 3.95; 5.62; 6.0; 6.37; 7.0; 7.6; 7.85; 8.15 m NMR spectrum as above.

Analogously, starting from a corresponding optically active (5 R) or (5 S) compound, the optically active (5 R) - or (5 S) -2-methyl-2-penem- Produce 3-car bonic acid, which can also be obtained by separating the race mat with an optically active base.

50 Example 6

(5 R, S) -2-methyl-2-penem-3-carboxylic acid sodium salt.

A solution of 50 mg (5 R, S) -2-methyl-2-penem-3-car-bonic acid in the equivalent amount of aqueous sodium hydrogen carbonate solution is evaporated in vacuo and dried under a high vacuum.

Example 7

(4R, S) -4-phenylacetylthio-2-oxo-azetidine.

A solution of 4.24 g (33 mM) (4R, S) -4-acetoxy-aceti-60 din-2-one in 20 ml water is added dropwise at room temperature with a solution of 5 g (33 mM) phenylthioacetic acid in 33 ml IN aqueous sodium hydroxide solution was added and the mixture was stirred at the same temperature overnight. The precipitated title compound is filtered off and recrystallized twice from ethylene chloride-hexane. Melting point 78 °; IR spectrum (CH2C12),: absorption bands at 3.0; 5.65; 5.95; 6.73; 7.15; 7.5; 7.87; 8.65; 9.21; 10.25; 10.6; 11.15 n-

19th

646 173

Example 8

2 - [(4 R, S) -4-phenylacetylthio-2-oxo-l-azetidinyl] -2-hydroxy-acetic acid p-nitrobenzyl ester.

At room temperature, a solution of 1.244 g (5.62 mM) (4R, S) -4-phenylacetylthio-2-oxo-azetidine in 42 ml toluene and 11 ml dimethylformadide with 2.87 g (11.24 mM) 2- Ethoxy-2-hydroxy-acetic acid p-nitrobenzyl ester added. After addition of freshly dried molecular sieves A4, the mixture is stirred under nitrogen overnight at room temperature. The molecular sieves are filtered off and the filtrate is evaporated in vacuo. The residue is dried under high vacuum and chromatographed on silica gel with toluene-ethyl acetate 9: 1 and 4: 1. After elution of unreacted p-nitrobenzyl 2-ethoxy-2-hydroxyacetic acid, the title compound is eluted with the following physicochemical properties: TLC: Rf = 0.38 (toluene-ethyl acetate 1: 1); IR spectrum (CH2C12): absorption bands at 2.85; 2.95; 5.6; 5.7 (sh); 5.9; 6.55; 7.4 n. This product still contains a little p-nitrobenzyl 2-ethoxy-2-hydroxy-acetic acid, but can be used in the following reaction without further purification.

Example 9

2- [(4R, S) -4-phenylacetylthio-2-oxo-l-azetidinyl] -2-tri-phenyl-phosphoranylidene-acetic acid-p-nitrobenzyl ester.

a) A solution of 522 mg (1.21 mM) of 2 - [(4R, S) -4-phenylacetylthio-2-oxo-1-azetidinyl] -2-hydroxyacetic acid p-nitrobenzyl ester in 10 ml of absolute dioxane added to a solution of 1.5 g of poly Hunig base in 5 ml of absolute dioxane which had already been stirred for 30 minutes. After adding a solution of 0.304 ml (3.5 equivalents) of thionyl chloride in 8 ml of absolute dioxane, the reaction mixture is stirred for 3 hours at room temperature and under nitrogen. The poly-Hunig base is filtered off and the filtrate is evaporated in vacuo. The 2 - [(4R, S) -4-phenylacetylthio-

2-oxo-1-azedidinal] -2-chloroacetic acid p-nitrobenzyl ester is used in the next reaction without further purification. TLC: Rf = 0.62 (toluene-acetylacetate 1: 1); IR spectrum (in CHiCl2): absorption bands at 5.61; 5.70; 6.25; 6.55; 7.45; 9.0 ji.

b) The crude 2 - [(4R, S) -4-phenylacetylthio-2-oxo-l-azetidinyl] -2-chloroacetic acid p-nitrobenzyl ester obtained is dissolved in 25 ml of absolute dioxane, with 481 mg of triphenylphosphine and 2 g of poly - Hunig base added and stirred overnight at 50 ° under nitrogen. The poly-Hunig base is filtered off, washed with dioxane and the filtrate and washing liquid are evaporated together in vacuo. The residue is chromatographed on silica gel with toluene-ethyl acetate 9: 1.4: 1 and 1: 1 and gives the title compound with the following physicochemical properties: TLC: Rf: = 0.27 (toluene-ethyl acetate 1: 1); IR spectrum (CH2C12): absorption bands at 3.33; 5.70; 5.90; 6.15; 6.57; 6.68; 6.96; 7.29; 7.42; 7.90; 8.25; 8.40; 9.05; 9.25; 9.70; 9.85; 10.0 jn.

Example 10

(5R, S) -2-benzyl-2-penem-3-carboxylic acid p-nitrobenzyl ester.

A solution of 268 mg (0.167 mM) of 2 - [(4 R, S) -4-phenylacetylthio-2-oxo-l-azetidinyl] -2-triphenylphosphoranyl-denacetic acid p-nitrobenzyl ester in 75 ml of absolute toluene is added added a catalytic amount of hydroquinone and stirred under nitrogen at 90 ° for 36 hours. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel with toluene-ethyl acetate 19: 1. The title compound is obtained in the form of colorless crystals with the following physicochemical properties: Melting point: 115 ° (from methylene chloride diethyl ether). IR

Spectrum (CH2C12): absorption bands at 3.33; 3.45; 5.6; 5.83; 6.25; 6.36; 6.58; 7.45; 7.65; 8.4; 8.85; 9.45; 9.95; 11.75. Nuclear Magnetic Resonance Spectrum (in CDC13 / 100 Mc; in ppm): 8.18.2H, d, J = 9 Hz; 7.58.2H, d, J = 9 Hz; 7.24.5 H, s; 5.57.1H, qu, Jcis s = 4 Hz, Jtrans = 2 Hz; 5.35.2H, Ab; 4.17; 2H, AB; 3.59, 2H, ABX; JAX = 2Hz, JBX = 4 Hz.

Example 11 (5R, S) -2-benzyl-2-penem-3-carboxylic acid.

io A solution of 78 mg (5R, S) -2-benzyl-2-penem-3-carbonic acid p-nitrobenzyl ester in 4.5 ml of absolute ethyl acetate is mixed with 3 ml of 0.2 M aqueous sodium bicarbonate solution and 150 mg 10% palladium / carbon catalyst was added and the mixture was stirred at atmospheric pressure for 30 minutes under 15 hydrogen. The hydrogenation mixture is filtered off from the catalyst over diatomaceous earth and washed with 2 ml of 0.2 M sodium hydrogen carbonate solution and ethyl acetate. The aqueous solution is separated off from the filtrate, acidified with 0.1 M aqueous citric acid solution and exhaustively extracted with 20 methylene chloride. The combined methylene chloride extracts are dried over sodium sulfate, filtered, evaporated in vacuo and dried in a high vacuum. The title compound is obtained in the form of colorless needles and has the following physicochemical properties: melting point 113-132 °; IR spectrum (CH2C12): absorption bands at 5.6; 6.0; 6.42; 7.45; 7.87; 8.43 p ..

Example 12 (4R, S) -4- (2-Furoylthio) -2-oxo-azetidine.

30 A solution of 5.15 g (35 mM) (4R, S) -4-acetoxyacetin-din-2-one in 20 ml of water is added dropwise under nitrogen at room temperature with a solution of 6.4 g (50.7 mM ) Furan-2-thiocarboxylic acid in 51 ml of 1N sodium hydroxide solution and stirred at the same temperature for 4 to 6 hours. The reaction mixture is extracted exhaustively with methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel with toluene-ethyl acetate 4: 1 and gives the title compound of melting point 94-95 °. TLC: Rf = 0.34 (toluene-ethyl acetate 2: 3); IR spectrum (CH2C12): absorption bands at 2.97; 5.6; 6.05; 6.37; 6.85 ji.

Example 13

45 2- [(4R, S) -4- (2-furoylthio) -2-oxo-l-azetidinyl] -2-hydroxy-acetic acid-p-nitrobenzyl ester.

At room temperature, 2.4 g of (4R, S) -4- (2-furoyl-thio) -2-oxo-azetidine are mixed in with a solution of 7.6 g of 2-ethoxy-2-hydroxy-acetic acid p-nitrobenzyl ester 150 ml T oluol and 50 38 ml dimethylformamide added. After adding freshly dried molecular sieves, the mixture is stirred under nitrogen for 15 hours at room temperature and then for 2 hours at 50 °. The molecular sieves are filtered off, washed with toluene and the filtrate and washing liquid are evaporated together in vacuo. The residue is chromatographed on 200 g of silica gel with toluene-ethyl acetate 9: 1 to 8: 2. After elution of unreacted p-nitro-benzyl 2-ethoxy-2-hydroxyacetic ester, the title compound is eluted with the following physicochemical properties: TLC: Rf = 0.33 (toluene-ethyl acetate 2: 3); IR spectrum (CH2C12): absorption bands at 2.87; 5.52; 5.6; 6.05; 6.55; 6.85 and 7.42 ji.

65

Example 14

2 - [(4R, S) -4- (2-furoylthio) -2-oxo-l-azetidinyl] -2-tri-phenyl-phosphoranylidene-acetic acid p-nitrobenzyl ester.

a) A solution of 4.9 g of 2 - [(4R, S) -4- (2-furoylthio) -2-oxo-1-azetidinyl] -2-hydroxyacetic acid p-nitrobenzyl ester in

646173

20th

90 ml of absolute dioxane is added to a solution of 18 g of poly Hunig base in 45 ml of absolute dioxane which has already been stirred for 30 minutes. After adding a solution of 3.45 ml of thionyl chloride in 30 ml of absolute dioxane, the reaction mixture is stirred for one hour at room temperature and under nitrogen. The poly-Hunig base is filtered off and the filtrate is evaporated in vacuo. IR spectrum (in CH2C12): absorption bands at 5.57; 6.02; 6.55; 7.4; 8.9; 11.4 h.

b) The crude 2 - [(4R, S) -4- (2-FuroyIthio) -2-oxo-l-azetidinyl] -2-chloroacetic acid p-nitrobenzyl ester obtained is dissolved in 216 ml of absolute dioxane, together with 18 g Poly-Hunig base stirred for 30 minutes under nitrogen and after adding 6.15 g of triphenylphosphine stirred for a further 15 hours at 50 ° under nitrogen. The poly-Hunig base is filtered off, washed with dioxane and the filtrate and washing liquid are evaporated together in vacuo. The residue is chromatographed on 200 g of silica gel with toluene-ethyl acetate 8: 2 and 7: 3 and gives the title compound with the following physicochemical properties: TLC: Rf = 0.35 (toluene-ethyl acetate 2: 3); IR spectrum (CH2C12): absorption bands at 5.67; 6.02; 6.15; 6.57; 7.42; 9.02; 9.25 and 9.85 \ i.

20th

Example 15

(5R, S) -2-fur-2-yl-2-penem-3-carboxylic acid p-nitrobenzyl ester.

A solution of 1 g (1.54mM) 2 - [(4R, S) -4- (2-furoyl-thio) -2-oxo-l-azetidinyl] -2-triphenylphosphoranylidenesacetic acid p-nitrobenzyl ester in 450 ml of absolute toluene a catalytic amount of hydroquinone is added and the mixture is stirred at 90 ° under nitrogen for 48 hours. The solvent is evaporated in vacuo and the residue is chromatographed on 50 g of silica gel with toluene-ethyl acetate 19: 1. The title compound is obtained in the form of crystals formed, having the following physicochemical properties: Melting point: 161-163 ° (diethyl ether-methylene chloride); TLC: Rf = 0.64 (toluene-ethyl acetate 2: 3; IR spectrum (CH2C12): absorption bands at 5.57; 5.85; 6.55; 7.42; 7.62; 8.2; 8, 35 and 8.5 H; NMR spectrum (in CDC13 / 100 Mc; in ppm): 8.22 = 2H, m; 7.75-7.5 = 4H, m; 6.55 = 1H; dd; 5 , 68 = 1H, dd; 5.37, 2H, m; 3.7 = 2H, m.

Example 16

(5R.S) -2-fur-2-yl-2-penem-3-carboxylic acid.

A solution of 100 mg (5R, S) -2-fur-2-yl-2-penem-3-carboxylic acid p-nitrobenzyl ester in 6 ml of absolute ethyl acetate is mixed with 4 ml of 0.2 N aqueous sodium hydrogen carbonate solution and 200 gmg 10% palladium / carbon catalyst was added and the mixture was stirred at atmospheric pressure for 75 minutes under hydrogen. The hydrogenation mixture is filtered off from the catalyst via diatomaceous earth, washed with 0.2 N sodium hydrogen carbonate solution and ethyl acetate, the filtrate and washing liquid are combined and the phases are separated. The aqueous phase is washed with methylene chloride, acidified with 5% aqueous citric acid solution and extracted with methylene chloride. The methylene chloride phases are dried over sodium sulfate, filtered, evaporated in vacuo and dried in a high vacuum. The title compound obtained has the following physicochemical properties: TLC: Rf = 0.34 (toluene-ethyl acetate-acetic acid 60: 40: 5) IR spectrum (KBr): absorption bands at 3.35-3.55; 5.6; 5.95; 6.57; 7.07; 7.7; 7.82; 8.15; 8.35 \ i; NMR spectrum (DMSO d6 / 100 Mc; in ppm); 7.9.1H, m; 7.6.1H, m; 6.74; 1H, m; 5.75.1H, m; 4.0-3.4.2H, m.

Example 17

(4R, S) -4- (3-Dimethylaminobenzoylthio) -2-oxoazetidine.

25th

A solution of 616 mg (4.77 mM) (4R, S) -4-acetoxy-azetidin-2-one in 13 ml of water is added dropwise at 0 ° with a solution of 864 mg (4.77 mM) of 3-dimethylaminothiobic -zoic acid in 4.77 ml IN sodium hydroxide solution and 5 ml s tetrahydrofuran and stirred at room temperature overnight. The reaction mixture is extracted with 50 ml of methylene chloride. The organic phase is washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel with toluene-ethyl acetate 9: 1, 4: 1 and 2: 1 and gives the title compound which, after recrystallization from methylene chloride pentane, is obtained in the form of green-yellow crystals with a melting point of 117 °. IR spectrum (CH2C12): absorption bands at 2.95; 3.5; 5.63; 6.03; 6.25; 6,68,7,0; 15 7.40; 8.28; 8.62; 10.22; 10.82; 11.10 (x.

Example 18

2- [4R, S) -4- (3-Dimethylaminobenzoylthio) -2-oxo-l-aazeididinyl] -2-hydroxyacetic acid p-nitrobenzyl ester.

At room temperature, a solution of 305 mg (1.38 mM) (4R, S) - (3-dimethylaminobenzoylthio) -2-oxo-azetidine in a mixture of 8 ml of toluene and 2 ml of dimethylformamide with 714 mg (2, 8 mM) 2-ethoxy-2-hydroxy-acetic acid p-nitrobenzyl ester was added. After addition of freshly dried molecular sieves A4, the mixture is stirred under nitrogen overnight at room temperature. The molecular sieves are filtered off, washed with toluene and the filtrate and washing liquid are evaporated together in vacuo. The residue is chromatographed on silica gel with toluene and toluene-ethyl acetate 9: 1 and 4: 1. After elution of unreacted p-nitro-2-ethoxy-2-hydroxyacetic acid, the title compound is eluted, which still contains some p-nitrobenzyl 2-ethoxy-2-hydroxyacetate, but without further purification into the next one Reaction can be used: TLC: Rf = 0.33 (toluene-ethyl acetate 1: 1); IR spectrum (CH2C12): absorption bands at 2.86; 3.42; 5.62; 5.69; 6.03; 6.23; 6.54; 7.41; 8.25; 9.15; 10.20; 10.83; 11.22 (i. Recrystallization from methylene chloride-diethyl ether gives 4o the pure title compound in the form of red-yellow plates with a melting point of 148 °.

Example 19

2- [(4R, S) -4- (3-Dimethylaminobenzoylthio) -2-oxo-l-aze-45 tidinylJ-2-chloroacetic acid p-nitrobenzyl ester.

A solution of 699 mg of 2 - [(4R, S) -4- (3-dimethylamino-benzoylthio) -2-oxo-l-azetidinyl] -2-hydroxyacetic acid p-ni-trobenzyl ester in 10 ml of absolute dioxane becomes one already stirred for 30 minutes solution of 2 g of poly-Hunig base 50 in 7.5 ml of absolute dioxane. After slowly adding 0.38 ml (3.5 equivalents) of thionyl chloride, the reaction mixture is stirred for 1.5 hours at room temperature and under nitrogen. The poly-Hunig base is filtered off and the filtrate is evaporated in vacuo. The title 55 compound obtained is used in the next reaction without further purification. TLC: Rf = 0.62 (toluene-ethyl acetate 1: 1); IR-. Spectrum (in CH2Clo): absorption bands at 3.4; 5.62; 5.67; 6.0; 6.25; 6.55; 6.68; 7.45; 7.65; 8.30; 8.50; 9.0; 10.4; 10.85; 11.75 ji.

60

Example 20

2- [(4R, S) -4- (3-Dimethylaminobenzoylthio) -2-oxo-l-azetidinylJ-2-triphenylphosphoranylideneacetic acid p-nitro-benzyl ester.

65 A solution of 747 mg of the crude 2 - [(4R, S) ~ 4- (3-dimethylaminobenzoylthio) -2-oxo-1-azetidinyl] -2-chloroacetic acid p-nitrobenzyl ester obtained in 30 ml of absolute dioxane is mixed with 2 g poly Hunig base and 614 mg triphenyl

21st

646173

added phosphine and stirred overnight at 50 ° under nitrogen. The poly-Hunig base is filtered off and the filtrate is evaporated in vacuo. The residue is taken up in methylene chloride, washed with aqueous sodium carbonate solution, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel with toluene-ethyl acetate 9: 1 and 4: 1 and gives the title compound as a green-yellow oil with the following physicochemical properties: TLC Rf = 0.23 (toluene-ethyl acetate 1: 1); IR spectrum (CH2C12): absorption bands at 3.45; 5.69; 6.02; 6.23; 6.57; 6.68; 6.97; 7.42; 8.28; 9.03; 9.25; 10.83 \ i organic phases are dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel with toluene-ethyl acetate 9: 1.4: 1 and 7: 3 and gives the title compound with the following phy-5 sikochemical properties. TLC: Rf = 0.23 (toluene-ethyl acetate 1: 1); IR spectrum (CH2C12): absorption bands at 2.95; 3.40; 5.6; 5.77; 5.88; 6.95; 7.10; 7.30; 7.42; 8.10; 8.30; 8.60; 9.35; 10.20; 10.55; 11.15 yes ..

10th

Example 21

(5R, S) -2- (3-dimethylaminophenyl) -2-penem-3-carboxylic acid p-nitrobenzyl ester.

A solution of 448 mg (0.64 mM) 2 - [(4R, S) -4- (3-dimethylaminobenzoylthio) -2-oxo-1-azetidinyl] -2-triphenyl-phosphoranylideneacetic acid p-nitrobenzyl ester in 100 ml of absolute toluene is mixed with a catalytic amount of hydroquinone and stirred under nitrogen at 90 ° for 90 hours. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel with toluene-ethyl acetate 19: 1. The title compound is obtained in the form of colorless crystals with the following physicochemical properties: melting point 77 ° (from methylene chloride-diethyl ether-pentane); TLC: Rf = 0.55 (toluene-ethyl acetate 1: 1); IR spectrum (CH2C12): absorption bands at 3.45; 5.6; 5.86; 6.25; 6.62; 6.72; 7.40; 7.68; 8.39; 8.45; 8.53; 9.10; 9.75; 10.05; 11.8 h; Nuclear Magnetic Resonance Spectrum (in CDC13 / 100 Mc; in ppm): 8.06, 2H, d, J = 10Hz; 7.25.4H, m; 6.75.2H, d, J = 10Hz; 5.75, 1H, dd, J, = 4Hz, J2 = 2 Hz; 5.18.2H, AB, J = 14Hz; 3.9, 1H, dd, J, = 16 Hz, J2 = 4 Hz; 3.56.1H, dd, J, = 16 Hz, J2 = 2 Hz; 2.88.6H, s.

Example 22

(5R, S) -2- (3-dimethylaminophenyl) -2-penem-3-carboxylic acid.

A solution of 65 mg (0.15 mM) (5R, S) -2- (3-dimethylaminophenyl) -2-penem-3-carboxylic acid p-nitrobenzyl ester in 4 ml of absolute ethyl acetate is mixed with 3 ml of 0.2 M aqueous sodium hydrogen carbonate solution and 150 mg of 10% palladium / carbon catalyst were added and the mixture was stirred under normal pressure for 60 minutes under hydrogen. The hydrogenation mixture is filtered off from the catalyst over diatomaceous earth, washed with 2 ml of 0.2 M sodium hydrogen carbonate solution and ethyl acetate. The aqueous phase is separated off from the filtrate and washed with diethyl ether. The washed aqueous solution is acidified with 5% aqueous citric acid solution and extracted exhaustively with methylene chloride. The combined methylene chloride extracts are dried over sodium sulfate, filtered and evaporated in vacuo. The title compound obtained has the following physicochemical properties: IR spectrum (CH2C12): absorption bands at 3.4; 5.57; 5.77; 5.95; 6.25; 6.70; 7.40; 8.08; 8.28; 8.80; 9.05; 10.05 \ i.

Example 23

(4R, S) -4- (3-carbomethoxypropionylthio) -2-oxo-aceti

din.

A solution of 996 mg (7.48 mM) (4R, S) -4-acetoxy-azetidin-2-one in 5 ml of water is added dropwise at room temperature with a solution of 1.11 g (7.48 mM) 1 - 4-monomethyl thiosuccinic acid in 7.48 ml IN sodium hydroxide solution. The reaction solution is adjusted to pH 8 by adding IN sodium hydroxide solution and extracted exhaustively with methylene chloride. The combined

Example 24

2- [(4R, S) -4- (3-Carbomethoxypropiony Ithio) -2-oxo-l-azetidinyl] -2-hydroxyacetic acid p-nitrobenzyl ester.

At room temperature, 266 mg (1.23 mM) (4R, S) -4- (3-carbomethoxypropionylthio) -2-oxo-azetidine with a solution of 625 mg (2 eq.) 2-ethoxy-2- p-nitrobenzyl ester of hydroxyacetic acid in 8 ml of toluene and 2 ml of dimethylformamide. After addition of freshly dried molecular sieves A4, the mixture is stirred under nitrogen overnight at room temperature. The molecular sieves are filtered off and the filtrate is evaporated in vacuo. The residue is dried under high vacuum and chromatographed on silica gel with toluene-ethyl acetate 9: 1.4: 1 and 7: 3. After elution of unreacted p-nitrobenzyl 2-ethoxy-2-hydroxy-acetic acid, the title compound is eluted with the following physicochemical properties: TLC: Rf = 0.20 (toluene-ethyl acetate 1: 1); IR spectrum (CH2C12): absorption bands at 2.85; 3.4; 5.65; 5.75; 5.95; 6.60; 7.45; 8.30; 9.15 fi.

30 Example 25

2- [(4R, S) -4- (3-Carbomethoxypropionylthio) -2-oxo-l-azetidinylJ-2-triphenylphosphoranylidene-acetic acid-p-nitro-benzyl ester.

35 a) A solution of 446 mg (1.05 mM) 2 - [(4 R, S) -4- (3-carbomethoxypropionylthio) -2-oxo-1-azetidinyl] -2-hydroxy-acetic acid p-nitrobenzyl ester in 8 ml of absolute dioxane is added to a solution of 2 g of poly-Hunig base in 7 ml of absolute dioxane. After adding a solution of 0.26 ml of 40 (3.5 equivalents) of thionyl chloride in 8 ml of absolute dioxane, the reaction mixture is stirred for 100 minutes at room temperature and under nitrogen. The poly-Hunig base is filtered off and the filtrate is evaporated in vacuo. The crude 2 - [(4R, S) -4- (3-carbomethoxypropinylthio) -2-oxo-l-azetidin-45 yl] -2-chloroacetic acid p-nitrobenzyl ester, TLC: Rf = 0.47 (toluene-ethyl acetate 1: 1); IR spectrum (in CH2C12): absorption bands at 3.40; 5.65; 5.80; 5.95; 6.60; 7.45; 7.65; 8.15; 8.35; 8.50; 9.40; 10.0; 11.4 h, is used in the next reaction without further purification.

b) The crude 2 - [(4R, S) -4- (3-carbomethoxypropionylthio) -2-oxo-1-azetidinyl] -2-chloroacetic acid p-nitro-benzyl ester obtained is dissolved in 25 ml of absolute dioxane, 2 g of poly-Hunig base and 433 mg of triphenylphosphine were added and the mixture was stirred at 50 ° under nitrogen overnight. The Poly-Hünig-55 base is filtered off, washed with dioxane and the filtrate and washing liquid are evaporated together in vacuo. The residue is chromatographed on silica gel with toluene-ethyl acetate 9: 1.4: 1 and 1: 1 and gives the title compound with the following physicochemical properties: TLC: Rf 60 = 0.1 (toluene-ethyl acetate 1: 1) IR spectrum (CH2C12): absorption bands at 3.40; 5.70; 5.95; 6.20; 6.60; 7.00; 7.45; 7.90; 8.30; 9.05 and 9.30 | x.

Example 26

65 (5R, S) -2- (2-carbomethoxyethyl) -2-penem-3-carboxylic acid p-nitrobenzyl ester.

A solution of 272 mg (0.41 mM) 2 - [(4R, S) -4- (3-car-bomethoxypropionylthio) -2-oxo-1-azetidinyl] -2-triphenyl-

50

646 173

22

p-nitrobenzyl ester of phosphoranylidene acetic acid 100 ml of absolute toluene is mixed with a catalytic amount of hydroxyquinone and stirred under nitrogen at 90 ° for two days. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel with toluene-ethyl acetate 19: 1 and 9: 1. The title compound is obtained in the form of colorless crystals with a melting point of 125 ° (from methylene chloride diethyl ether); TLC: Rf = 0.47 (toluene-ethyl acetate 1: 1); IR spectrum (CH2C12): absorption bands at 3.30; 3.45; 5.60; 5.78; 5.85; 6.33; 6.56; 7.45; 7.65; 8.35; 8.80; 9.50 \ i; NMR spectrum (in CDC13 / 100 Mc; in ppm): 8.28.2H, d, J = 9Hz; 7.65; 2H, d, J = 9Hz; 5.70.1H, dd, J, = 2Hz, J2 = 4Hz; 5.40.2H, AB, J = 14Hz; 3.85.1H, ABX, J, = 16Hz, J2 = 4Hz; 3.74; 3H, s; 3.55; 1H, ABX, J, = 16Hz, J2 = 2Hz; 3.20.2H; 2.64; 2H.

Example 27

(5R, S) -2- (2-carbomethoxyethyl) -2-penem-3-carboxylic acid.

A solution of 50 mg (5R, S) -2- (2-carbomethoxy-eth-yl) -2-penem-3-carboxylic acid p-nitrobenzyl ester in 3 ml of absolute ethyl acetate is mixed with 3 ml of 2 M aqueous sodium hydrogen carbonate solution and 150 mg of 10% palladium / carbon catalyst were added and the mixture was stirred under normal pressure for 60 minutes under hydrogen. The hydrogenation mixture is filtered off from the catalyst via diatomaceous earth, washed with 2 ml of 2 M sodium hydrogen carbonate solution and ethyl acetate and the aqueous phase is separated from the filtrate and washing liquid. The aqueous solution is washed once with diethyl ether, acidified with 5% aqueous citric acid solution and extracted exhaustively with methylene chloride. The combined methylene chloride extracts are dried over sodium sulfate, filtered, evaporated in vacuo and dried in a high vacuum. The title compound obtained has the following physicochemical properties: IR spectrum (CH2C12): 3.45; 5.57; 5.75; 5.95; 6.35; 7.0; 7.70; 8.35; 8.50; 9.50 h; UV spectrum in ethanol: Xmax at 262 and 304 nm.

Example 28

(4R, S) -4-benzoylthio-2-oxo-azetidine.

A solution of 5.15 g (40 mM) (4R, S) -4-acetoxy-azetin-din-2-one in 20 ml water is added dropwise at 0 ° with a solution of 5.5 g (40 mM) thiobenzoic acid added in 40 ml IN sodium hydroxide solution. The reaction mixture is adjusted to pH about 7 and stirred overnight. The title compound which precipitates is filtered off, washed free of alkali with cold water and recrystallized from methylene chloride / hexane. Melting point: 104-105 °; TLC: Rf = 0.56 (toluene-ethyl acetate 1: 1); IR spectrum (CH2C12): absorption bands at 2.92; 5.57; 5.95; 6.20; 6.27; 8.22; 8.45; 10.85; 11.10 \ i.

Example 29

2- [(4R, S) -4-benzoylthio-2-oxo-l-azetidinyl] -2-hydroxy-acetic acid p-nitrobenzyl ester.

A solution of 2.35 g (11.38 mM) (4R, S) -4-benzoyl-thio-2-oxo-azetidine and 6.45 g of 2-ethoxy-2-hydroxyacetic acid re-p-nitrobenzyl ester in one A mixture of 120 ml of dry toluene and 30 ml of dimethylformamide is mixed with freshly dried molecular sieves and stirred under nitrogen overnight at room temperature and then at 50 ° for 2 hours. The molecular sieves are filtered off and the filtrate is evaporated in vacuo. The residue is dried under high vacuum and chromatographed on silica gel with toluene-ethyl acetate 9: 1 and 3: 1. After elution of unreacted p-nitrobenzyl 2-ethoxy-2-hydroxy-acetic acid, the title compound is eluted with the following physicochemical properties: TLC: Rf = 0.56 (toluene-ethyl acetate 1: 1); IR spectrum (CH2C12): absorption bands at 2.85; 5.6; 5.67; 5.95; 6.00; 6.52; 7.40; 8.25; 9.00; 9.15; 10.00; 11.70 i.

5

Example 30

2- [(4R, S) -4-benzoylthio-2-oxo-l-azetidinylJ-2-triphenyl-phosphoranylidene-acetic acid-p-nitrobenzyl ester.

a) A solution of 3 g of 2- [4R, S) -4-benzoylthio-2-oxo-l-io azetidinyl] -2-hydroxyacetic acid p-nitrobenzyl ester in 50 ml

Dioxane is added to a mixture of 10 g poly Hunig base in 50 ml dioxane. After adding a solution of 3 ml of thionyl chloride in 50 ml of dioxane, the reaction mixture is stirred for 5 hours at room temperature. The poly-Hunig base 15 is filtered off and the filtrate is evaporated in vacuo.

b) The crude 2 - [(4R, S) -4-benzoylthio-2-oxo-l-azetidinyl] -2-chloroacetic acid p-nitrobenzyl ester obtained is dissolved in 100 ml of dioxane, with 10 g of poly Hunig base and 3, 5 g of triphenylphosphine were added and the mixture was stirred at 50 ° for 15 hours. The

20 poly Hünig base is filtered off and the filtrate is evaporated in vacuo. The residue is chromatographed on silica gel with toluene-ethyl acetate 9: 1 and 3: 2 and gives the title compound with the following physico-chemical properties: TLC: Rf = 0.28 (toluene-ethyl acetate 1: 1); IR spec-25 spectrum (CH2C12): absorption bands at 5.67; 6.00; 6.15; 6.55; 7.42; 8.30; 9.05; 9.25 and 11.05 (i.

Example 31

(5R, S) -2-phenyl-2-penem-3-carboxylic acid-p-nitrobenzyl-

30th

ester.

A solution of 2.40 g (3.63 mM) of 2 - [(4R, S) -4-benzoyl-thio-2-oxo-1-azetidinyl] -2-triphenyl-phosphoranylidene-acetic acid-p-nitrobenzyl ester A catalytic amount of hydroquinone is added to 800 ml of dry toluene and the mixture is stirred at 90 ° for two days. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel with toluene-ethyl acetate 19: 1. The title compound is obtained in the form of colorless crystals with the following physicochemical properties. Mp 182-183 ° (from methylene chloride / diethyl ether); TLC: Rf = 0.67 (toluene-ethyl acetate 1: 1); UV spectrum (ethanol): Ä, max = 258 nm (s = 17 256); 327 nm (s = 8112); IR spectrum (CH2C12): absorption bands at 5.55; 5.82; 6.55; 7.40; 7.65; 8.35; 8.45; 9.15; 9.851x; NMR spectrum (in CDC13 / 100 Mc; in ppm): 8.10, d, 45 J = 9Hz, 2H; 7.38, m, 7H; 5.78, qu, J = 4Hz, J2 = 2Hz, 1H; 5.29, d, J = 14Hz, 1H; 5.12, j = 14Hz, 1H; 3.88, qu, J = 16Hz, J2 = 4Hz, 1H; 3.60, qu, J, = 16 Hz, J2 = 2 Hz, 1H.

40

50

Example 32 (5 R, S) -2-phenyl-2-penem-3-carboxylic acid.

A suspension of 200 mg (5R, S) -2-phenyl-2-penem-3-carboxylic acid p-nitrobenzyl ester in 12 ml of ethyl acetate and 8 ml of 0.2 M aqueous sodium bicarbonate solution is flushed with nitrogen, with 350 mg of 10% Palladium / carbon 55 catalyst was added and the mixture was stirred under normal pressure for 1 hour and 30 minutes under hydrogen. The hydrogenation mixture is filtered off from the catalyst over diatomaceous earth, washed with 2 ml of water and 5 ml of ethyl acetate, and the filtrate and washing liquid are combined. The aqueous phase 60 is separated off, acidified with 5% aqueous citric acid solution and extracted with methylene chloride. The organic phase is dried over sodium sulfate, filtered, evaporated in vacuo and dried in a high vacuum. The title compound obtained has the following physicochemical properties: Melting point: 127-128 ° (from acetone / diethyl ether); UV spectrum (ethanol): A, max = 323 mji (s = 7310); 246 m | j. sh (s = 9570); 235 m | i (s = 10 470): IR spectrum

65

23 646173

(KBr); Absorption bands at 3.50; 5.60; 6.00; 6.45; 6.72; 20 ml of dry dioxane dissolved, with 2 g of poly Hunig base and

6.97; 7.67; 7.85; 8.27; 9.65; 11.05; 13.10; 13.30; 13.95; 14.45h; 0.5 triphenylphosphine added and overnight at 50 °

Nuclear Magnetic Resonance Spectrum (CDC13 / 100Mc; in ppm): 7.42, m, 5H; 5.78. The poly-Hünig base is filtered off and the filtrate in qu, J | = 4Hz, J2 = 2Hz, 1H; 3.88, qu, Ji = 16Hz, J2 = 4Hz, 1H; Evaporated vacuum. The residue is added to silica gel

3.60, qu, J, = 16Hz, J2 = 2Hz, 1H. s Toluene ethyl acetate 9: 1 to 1: 1 chromatographed to give the title compound with the following physico-chemical

Example 33 Properties: TLC: Rf = 0.15 (toluene-ethyl acetate 1: 1); IR

(4R, S) -4-acetoxyacetylthio-2-oxo-azetidine. Spectrum (CH2C12): absorption bands at 5.70; 6.15; 6.55;

A solution of 8.5 g (0.065 mol) (4R, S) -4-acetoxyaze- 6.98; 7.45; 8.20; 8.85; 9.05

tidin-2-one in 50 ml acetone is with a pre-cooled Lö- 10

solution of 13.4g (0.1mole) acetoxy-thioacetic acid in 100ml Example 36

Added in sodium hydroxide solution and at room temperature- (5R, S) -acetoxymethyl-2-penem-3-carboxylic acid-p-nitro-

stirred for 3 hours. The reaction mixture is with 3 benzyl esters.

extracted 100 ml of methylene chloride. The combined orga- A solution of 0.656 g (1 mM) 2- [4R, S) -4-acetoxyacet-

phases are dried over sodium sulfate and 15 ylthio-2-oxo-l-azetidinyl] -2-triphenylphosphoranylidene-es-

evaporated in vacuo. The residue is chromatographed on silica gel p-nitrobenzyl acetate in 100 ml of dry toluene, and the mixture is chromatographed with toluene / ethyl acetate 4: 1 and gives a catalytic amount of hydroquinone and

Title compound with the following physicochemical egg stirred at 90 ° for 36 hours. The solvent becomes: TLC: Rf = 0.34 (toluene-ethyl acetate 1: 1); IR- evaporated in vacuo and the residue on silica gel with

Spectrum (CH2C12): absorption bands at 2.95; 5.6; 5.72; 20 toluene-ethyl acetate 9: 1 chromatographed. You get that

5.9; 8.20 h title compound in the form of colorless crystals with the following

The acetoxythioacetic-physicochemical properties used as starting material: mp 127-128 ° (can be prepared from methyl acid as follows: enchloride / diethyl ether); TLC: Rf = 0.53 (toluene-ethyl acetate through an ice-cold solution of 6.11 g (0.1 mol) of potassium 1: 1); UV spectrum (ethanol): Xmûx = 319 nm (e = 9173); 262 hydroxide in 3 ml of water and 55 ml of ethanol becomes 45 nm for 45 (e = 11 897); IR spectrum (CH2C12): Absorption ban minutes of hydrogen sulfide passed. To the ice obtained at 5.60; 5.75; 5.85; 6.30; 6.55; 7.45; 7.60; 8.20 n; NMR cold solution of potassium hydrogen sulfide is under stirring spectrum (in CDC13 / 100 Mc; in ppm): 2.14, s, 3H; 3.58, dd, within 20 minutes a solution of 3.73 g (0.027 mol) JA = 16Hz, JB = 2Hz, 1H; 3.84, dd, JA = 16Hz, Jc = 4Hz, 1H; Acetoacetyl chloride added dropwise in 20 ml of dry dioxane. 5.00-5.60, two overlapping AB quartets, 4H; 5.72, qu, After stirring for one hour at room temperature, the 30 JB = 2Hz; Jc = 4Hz, 1H; 7.63, d, J = 8Hz, 2H; 8.22, d, reaction mixture extracted with diethyl ether, with chilled J = 8Hz, 2H.

ter 2N sulfuric acid acidified and extracted with diethyl ether. The organic phase is dried and evaporated. Example 37 and the acetoxy-thioacetic acid obtained without further pure (5R, S) -2-acetoxymethyl-2-penem-3-carboxylic acid.

used in the above reaction. 35 A solution of 100 mg (0.26 mM) (5R, S) -2-acetoxy-

methyl-2-penem-3-carboxylic acid pnitrobenzyl ester in 6 ml

Example 34 Ethyl acetate is mixed with 4 ml of 0.2 M aqueous sodium hydrogen

2- [(4R, S) -4-acetoxyacetylthio-2-oxo-l-azetidinyl] carbonate solution and 200 mg 10% palladium / carbon ca

P-nitrobenzyl 2-hydroxyacetic acid ester. Talysator offset and at normal pressure for 40 minutes

A solution of 0.44 g (2.17 mM) (4R, S) -acetoxyacetyl- 40 was stirred under hydrogen. The hydrogenation mixture is filtered through thio-2-oxo-azetidine and 1.23 g of 2-ethoxy-2-hydroxy-acetic acid diatomaceous earth from the catalyst. The aqueous re-p-nitrobenzyl ester in a mixture of 25 ml of toluene and phase is mixed with 10 ml of 50% aqueous citric acid solution

5 ml of dimethylformamide is acidified with freshly dried mole and extracted with 3 times 20 ml of methylene chloride,

molecular sieves and added overnight under nitrogen. The organic phase is dried over sodium sulfate,

Room temperature and then triturated at 45 for 4 hours, evaporated in vacuo and evaporated in a high vacuum

Stirred 50 °. The molecular sieves are filtered off and this dries. The title compound obtained has the following physical

The filtrate is evaporated in vacuo. The residue has chemical properties: TLC: Rf = 0.16 (toluene-ethyl

dried in a high vacuum and on silica gel with toluene-ether-acetate-acetic acid 60: 40: 5); UV spectrum (ethanol): =

Chromatographed 9: 1 to 4: 1 ylacetate. After elution of 312 and 247 mu; IR spectrum (KBr): absorption bands of unreacted 2-ethoxy-2-hydroxy-acetic acid-p-nitro-50 at 3.45 b; 5.60; 5.72; 6.00; 6.40; 6.85; 7.25; 7.60; 7.80; 8.20; benzyl ester becomes the title compound with the following physical 8.30; 9.65 yes; NMR spectrum (DMSO d6 / lOOMc; in ppm):

Chemical properties eluted: TLC: Rf = 0.31 (toluene-2.00, s, 3H; 3.4, dd, JA = 16Hz; JB = 2Hz; 1H; 3.74, dd, JA = 16 ethyl acetate 1: 1); IR spectrum (CH2C12); Absorption bands Hz, Jc = 4Hz, 1H; 5.04, d, J = 15Hz, 2H; 5.63, qu, JB = 2Hz,

at 2.9; 5.6; 5.7; 5.90; 6.25; 6.55; 7.45; 8.25 \ i. 5j Jc = 4Hz, 1H.

Example 35 Example 38

2- [(4R, S) -4-acetoxyacetylthio-2-oxo-l-azetidinylJ -2-tri- (4R, S) -4-hexanoylthio-2-oxo-azetidine. phenyl-phosphoranylidene-acetic acid-p-nitrobenzyl ester. An ice-cold solution of 2.58 g (20 mM) (4R, S) -4-

a) A stirred mixture of 0.82 g (2 mM) 2 - [(4R, S) - acetoxyazetidin-2-one in 10 ml dioxane is added dropwise with 4-acetoxyacetylthio-2-oxo-l-azetidinyl] -2- hydroxyacetic acid - a cold-prepared solution of 2.64 g (20 mM) re-p-nitrobenzyl ester and 2 g poly-Hünig base in 20 ml dry-thiohexanoic acid in 10 ml 2N sodium hydroxide solution Negative Dioxane is mixed with a solution of 0.26 ml Thionyl sets and stirred at room temperature for 30 minutes. The re-chloride is added in 5 ml of dioxane. The reaction mixture is extracted with methylene chloride. The stirred for one hour at room temperature, the poly-Hünig-65 combined organic phases are filtered off over sodium sulfate base and the filtrate is evaporated in vacuo, dried and evaporated in vacuo. The residue b) The crude 2 - [(4R, S) -4-acetoxyacetyl-thio-2- obtained is chromatographed on silica gel with toluene-ethyl acetate. Oxo-l-azetidinyl] -2-chloroacetic acid p-nitrobenzyl ester is added to and gives the title link with the following physical

646173

24th

15

chemical properties. TLC: Rf = 0.43 (toluene-ethyl acetate 1: 1); IR spectrum (CH2C12): absorption bands at 3.00; 5.65; 5.85 | i.

Example 39

2 - [(4R, S) -4-hexanoylthio-2-oxo-l-azetidinyl] -2-hydroxy-acetic acid p-nitrobenzyl ester.

At room temperature, 2.38 g (11.84 mM) (4R, S) -4-hexanoylthio-2-oxo-azetidine and 6 g of 2-ethoxy-2-hydroxy-acetic acid p-nitrobenzyl ester are mixed in a mixture of 120 ml of toluene and 30 ml of dimethylformamide dissolved. After adding freshly dried molecular sieves, the mixture is stirred under nitrogen for 15 hours at room temperature and then for 2 hours at 50 °. The molecular sieves are filtered off, the filtrate is evaporated in vacuo and the residue is chromatographed on silica gel with toluene-ethyl acetate 9: 1 to 4: 1. After elution of unreacted p-nitrobenzyl 2-ethoxy-2-hydroxyacetic acid, the crude title compound is eluted with the following physicochemical properties: TLC: Rf = 0.47 (toluene-ethyl acetate 1: 1); IR spectrum (CH2C12): absorption bands at 2.85; 5.65; 5.75; 5,85,6,25; 6.58; 7.45 \ i.

Example 40

2- [(4R, S) -4-H.exanoylthio-2-oxo-l-azetid.inyl] -2-tri-phenylphosphoranylidene-acetic acid-p-nitrobenzyl ester.

a) A solution of 6.70 g of 2 - [(4R, S) -4-hexanoylthio-2-oxo-l-azetidinyl] -2-hydroxyacetic acid-p-nitrobenzyl ester in 100 ml of dioxane is stirred together with 15 g of poly-Hunig base and added dropwise with a solution of 6 ml of thionyl 30 chloride in 50 ml of dioxane. The reaction mixture is stirred for 5 hours at room temperature, the poly-Huenig base is filtered off and the filtrate is evaporated in vacuo.

35

b) The crude 2 - [(4R, S) -4-hexanoylthio-2-oxo-l-azetidinyl] -2-chloroacetic acid p-nitrobenzyl ester obtained is dissolved in 150 ml of dioxane, with 15 g of poly-Hunig base and 6 g Triphenylphosphine added and stirred overnight at 50 °. The poly Hunig base is filtered off and the filtrate is evaporated in vacuo. The residue is chromatographed on silica gel with toluene-ethyl acetate 9: 1 to 1: 1 and gives the title compound with the following physicochemical properties: TLC: Rf = 0.33 (toluene-ethyl acetate 1: 1); IR spectrum (CH2C12): absorption bands at 5.70; 5.9; 6.15; 6.57; 6.96; 7.45; 9.05; 9.25 H

Example 42 (5R, S) -2-pentyl-2-penem-3-carboxylic acid.

A solution of 800 mg (2.1 mM), (5R, S) -2-pentyl-2-pe-nem-3-carboxylic acid p-nitrobenzyl ester in 48 ml of ethyl acetate 5 is mixed with 32 ml of 0.2 M aqueous sodium hydrogen carbonate solution and 1.60 g of 10% palladium / carbon catalyst were added and the mixture was stirred under normal pressure for 60 minutes under hydrogen. The hydrogenation mixture is filtered off from the catalyst via diatomaceous earth. The aqueous phase is acidified with 10 80 ml of 5% aqueous citric acid solution and extracted with methylene chloride. The organic phase is dried over sodium sulfate, filtered, evaporated in vacuo and dried in a high vacuum. The title compound obtained is recrystallized from diethyl ether.

Melting point: 99-100 °; UV spectrum (ethanol):

Ä-max = 307 mja. (s = 5321); 257 m (i (s = 3712; IR spectrum (CH2C12): absorption bands at 2.75-4.25 (b); 5.60; 5.97; 6.40; 7.05; 7.70; 8 , 25; 8.32 h; NMR spectrum (CDC13 / 100 Mc, in ppm): 8.20, b, 1H; 5.63; qu, Jcis = 4Hz, Jtrans = 2Hz, 1H; 20 3.80; qu, Jgem = 16Hz, Jcis = 4Hz, 1H, 3.46, qu, Jgem = 16Hz, Jtrans = 2Hz, 1H; 283, m, Jgem = 14Hz, Jh, ch2 = 7Hz, 2H; 1.10-1, 80, m, 6H; 0.89, t, 3H.

25th

45

50

Example 41

(5R, S) -2-pentyl-2-penem-3-carboxylic acid p-nitrobenzyl ester.

A solution of 4.4 g (6.7 mM) of 2 - [(4R, S) -4-hexanoyl-thio-2-oxo-l-azetidinyl] -2-triphenyl-phosphoranylidene-acetic acid-p-nitrobenzyl ester A catalytic amount of hydroquinone is added to 2 liters of dry toluene and the mixture is stirred at 90 ° for two days. The solvent is evaporated off in vacuo and the residue is chromatographed on silica gel with toluene-ethyl acetate 19: 1. The title compound is obtained with the following physicochemical properties: TLC: Rf = 0.68 (toluene-ethyl acetate 1: 1); UV spectrum (ethanol): Xmax = 310 nm (e = 9759); 270 nm (e = 13,593); IR-60 spectrum (CH2 Cl2): absorption bands at 5.60; 5.85; 6.35; 6.57; 7.43; 7.65; 8.37 and 9.05 | i; NMR spectrum (in CDClj / 100 Mc; in ppm): 8.20, d, J = 8Hz, 2H; 7.60, d, J = 8Hz, 2H; 5.62, qu, Jcis = 4Hz, Jtrans = 2Hz, 1H; 5.44, d, J = 14Hz, 1H; 5.20; d, J = 14Hz, 1H; 3.80, qu, J = 16Hz, Jcis = 4Hz, 1H; 3.48, qu, J = 16Hz, Jtrans = 2Hz, 1H; 2.84, m, J = 14Hz, J = 7Hz, 2H, 1.10-1.70, m, 6H; 0.88, t, 3H.

65

Example 43

(4R, S) -4-tert-butylthioacetylthio-2-oxo-azetidine.

A solution of 3.79 g (28.3 mM) (4R, S) -4-acetoxyaze-tidin-2-one in 15 ml of dioxane is added dropwise with cooling to a solution of 5.74 g (35 mM) tert-butylthio-thioacetic acid in 35 ml IN sodium hydroxide solution and stirred at room temperature for 2 hours. The reaction mixture is extracted with methylene chloride. The organic phase is dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel with toluene-ethyl acetate 9: 1 to 3: 1 and gives the title compound with the following physicochemical properties. TLC: Rf = 0.39 (toluene-ethyl acetate 1: 1); IR spectrum (CH2C12); Absorption bands at 2.97, 3.42; 5,65,5,87; 8.62; 10.22 \ i.

The thiocarboxylic acid used as the starting material will be obtained as follows:

A mixture of 50 ml of pyridine and 150 ml of dry methylene chloride is saturated with hydrogen sulfide while cooling, and a solution of 10 g (0.06 mol) of tert-butylthioacetyl chloride in 50 ml of dry methylene chloride is added dropwise within 30 minutes. The reaction mixture is warmed to room temperature while passing through hydrogen sulfide and stirred for 2 hours. After acidification with 2N sulfuric acid, the organic phase is separated off, dried and evaporated in vacuo. The residue is used in the above reaction without further purification.

Example 44

2- [(4R, S) -4-tert-butylthioacetylthio-2-oxo-l-azetidin-yl] -2-hydroxy acetic acid and p-nitrobenzyl ester. - -—r

A solution of 4.8 g (20.5 mM) (4R, S) -4-tert-butylthio-acetylthio-2-oxo-azetidine and 11.6 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester in A mixture of 250 ml of dry toluene and 55 ml of dimethylformamide is mixed with freshly dried molecular sieves and stirred for 16 hours at room temperature and then for 2 hours at 50 °. The molecular sieves are filtered off, the filtrate is evaporated in vacuo and the residue is chromatographed on silica gel with toluene-ethyl acetate 4: 1. After elution of unreacted p-nitrobenzyl 2-ethoxy-2-hydroxy-acetic acid, the title compound is eluted with the following physicochemical properties: TLC:

25 646173

Rf = 0.38 (toluene-ethyl acetate 1: 1); IR spectrum (CH2C12): (ethanol): ^ max 314 mp. (e = 3918); 259 mu (3667); (IR spec

Absorption bands at 2.85; 5.62; 5.70; 5.95; 6.22; 6.55; 7.42; tram (KBr): absorption bands at 2.95.3.40; 3.95; 5.60;

8,30,9,25 and 11,75 ji. 6.02; 6.47; 6.95; 7.52; 7.87; 8.20; 14.05 h; NMR spectrum

(DMSO d6 / 100 Mc; in ppm): 5.62, qu, Jcis = 4Hz,

Example 45 5 Jtrans = ~ 2Hz, 1H; 4.20, d, Jgem = 14Hz, 1H; 3.83, d,

2 - [(4R, S) -4-tert-butylthioacetylthio-2-oxo-l-azetidine-Jgem = 14Hz, 1H; 3.80, Jgem = 16Hz, Jc; s = 4Hz, IH; 3.44, qu, ylJ-2-triphenylphosphoranylidene-acetic acid-p-nitrobenzyl ester Jgem = 16Hz, Jtrans = ~ 2Hz, 1H; 1.30, s, 9H.

a) A mixture of 9.46 g of 2 - [(4R, S) -4-acetylthio-2-

oxol-azetidinyl] -2-hydroxyacetic acid p-nitrobenzyl ester, Example 48

contaminated by some 2-ethoxy-2-hydroxy-acetic acid-ni- 10 (4R, S) -4- (4-p-nitrobenzyloxycarbonylamino-butyryl-

trobenzyl ester, and 15.2 g of poly Hunig base in 180 ml of dioxane thio) -2-oxo-azetidine.

is stirred for 30 minutes and with a solution of 2.6 ml. A pre-cooled solution of 1.1 g (8.52 mM) (4R, S) -4-

Thionyl chloride in 50 ml of dioxane. The reaction mi-acetoxyazetidin-2-one in 10 ml of dioxane is added dropwise with a little stirring at room temperature for 2 hours, the Po- a cold-prepared solution of 2.98 g (10 mM) 4-p-

ly-Hunig base is filtered off and the filtrate is vacuumed with 15 nitrobenzyloxycarbonylamino-thiobutyric acid in 10 ml of IN

steamed. Sodium hydroxide solution added and stirred at room temperature b) The crude 2 - [(4R, S) -4-tert-butylthioacetyl-11/1 hours obtained. The reaction mixture is exhausted-thio-2-oxo-1-azetidnyl] -2-chloroacetic acid p-nitrobenzyl ester extracted with methylene chloride. The combined organi is dissolved in 200 ml of dioxane, 15 g of poly-Hunig base and phases are dried over sodium sulfate and added in 6.125 g of triphenylphosphine and evaporated for 16 hours at 50 ° 20 vacuum. The residue is stirred on silica gel. The poly-Hunig base is filtered off and the filtrate toluene-ethyl acetate 9: 1.7: 2 and 1: 1 is chromatographed and evaporated in vacuo. The residue is chromatographed on silica gel to give the title compound with the following physico-chemical with toluene-ethyl acetate 9: 1 to 4: 1 and see properties. TLC: Rf = 0.33 (toluene-ethyl acetate gives the title compound with the following physico-chemical 1: 2); IR spectrum (CH2C12): absorption bands at 2.95; see properties: TLC: Rf = 0.27 (toluene-ethyl acetate 25 5.65; 5.80; 5.92; 6.25; 6.60; 7.45 and 8.15 [t.

1: 1); IR spectrum (CH2C12): absorption bands at 3.40; The thiocarboxylic acid used as the starting material

5,65,5,95; 6.12; 6.55; 7.40; 8.00; 8.20 | i. is obtained as follows:

a) A solution of 10.30 g (0.1 mM) 4-amino butter

Example 46 acid is dissolved in 300 ml of 1N sodium hydroxide solution with a (5R, S) -2-tert-butylthiomethyl-2-penem-3-carboxylic acid p-30 ice bath dropwise within 20 minutes with a solution of nitrobenzyl ester. of 25.87 (0.12 mM) p-nitrobenzyl chloroformate in 100 ml

A solution of 2.57 g (3.75 mM) of 2 - [(4R, S) -4-tert-but-dry dioxane was added. The reaction mixture becomes 3

ylthio-2-oxo-1-azetidinyl] -2-triphenylphosphoranyliden- stirred at room temperature for hours, washed with ethyl acetate

See acetic acid p-nitrobenzyl ester in 800 ml of dry toluene and acidified with 2N hydrochloric acid. The failing 4-p

a catalytic amount of hydroquinone is added 35 nitrobenzyloxycarbonylaminobutyric acid is filtered off and stirred at 90 ° for 17 hours. The solvent is recrystallized in and from ethyl acetate; Melting point

Vacuum evaporated and the residue on silica gel at 145-146 °.

Chromatographed toluene-ethyl acetate 9: 1. This gives the b) To a solution of 2.82 g (10 title compound after crystallization from methylene chloride / mM) cooled to -10 ° C. 4-p-nitrobenzyloxycarbonylaminobutyric acid in 50 ml of petroleum ether with the following physicochemical properties: dry methylene chloride becomes 2.2 g in succession (20 F. 150-152 °; TLC: Rf = 0.59 (toluene-ethyl acetate 1: 1); UV-mM) triethylamine and a solution of 1.4 ml (10 mM) IsoSpectrum (ethanol): A, max = 323 nm (e = 8084); 263 nm (s = butyl chloroformate in 20 ml dry methylene chloride added-13 313); IR spectrum (CH2C12): absorption bands at dripping. The reaction mixture is stirred for one hour and 3.37; 5.60; 5.85; 6.58; 7.45; 7.65; 8.45; 8.85 | i; NMR spec- subsequently followed by a strong sulfur water strand (in CDCI3 / IOO Mc; in ppm) for 2 hours: 8.20, d, J = 8Hz, 2H; 7, 60, 4 flow passed through. After acidification with 2N sulfur-d, J = 8Hz, 2H; 5.61, qu, Jcis = 4Hz, Jtrans = 2Hz, 1H; 5.46, acid, the organic phase is separated off, dried and d, Jgem = 14Hz, 1H; 5.24, d, Jgem = 14Hz, 1H; 4.08, d, Jgem = evaporated in vacuo. The 4-p-nitrobenzyloxy-14Hz, 1H; 3.86, d, Jgem = 14Hz, 1H; 3.80, m, Jgem = 16Hz, Jcis carbonylamino-thiobutyric acid can without further purification = 4Hz, 1H; 3.52, m, Jgem = 16Hz, Jtrans = 2Hz, 1H; 1.32, s. be processed further.

9H.

Example 49

Example 47 2 - [(4R, S) -4- (4-p-nitrobenzyloxycarbonylaminobutyryl-

(5R, S) -2-tert-butylthiomethyl-2-penem-3-carboxylic acid. thio) - 2-oxo-l-azetidinyl] - 2-hydroxyacetic acid-p-nitrobenz-

A solution of 116 mg (0.28 mM) (5R, S) -2-tert-butyl ester.

ylthiomethyl-2-penem-3-carboxylic acid p-nitrobenzyl ester in 55

10 ml of ethyl acetate is mixed with 3.6 ml of 0.2 M aqueous sodium. At room temperature, 2.724 g (7.42 mM) (4R, S) -

hydrogen carbonate solution and 183 mg of 10% palladium / 4 (4-p-nitrobenzyloxycarbonylaminobutyrylthio) - 2-oxo-carbon catalyst and added at normal pressure during 60 azetidine and 4.35 g of 2-ethoxy-2-hydroxy-acetic acid-p-nitro

Minutes under hydrogen. The hydrogenation mixture of benzyl ester in 120 ml of toluene and 30 ml of dimethylformamide is filtered off from the catalyst over diatomaceous earth. The 60 solved. After adding freshly dried molecular sieves

aqueous phase is washed with diethyl ether, with 5% ben the mixture is acidified under nitrogen overnight with aqueous citric acid solution and extracted with methyl room temperature and then for 2 hours with enchloride. The organic phase is stirred over sodium 50 °. The molecular sieves are filtered off, the filtrate is dried over sulfate, filtered, evaporated in vacuo and is evaporated in vacuo and the residue on silica

dried in a high vacuum. The title compound obtained gel with toluene-ethyl acetate 9: 1.8: 1 and 1: 1 chromatographic

has the following physicochemical properties: After elution of unreacted 2-ethoxy-2-

point 132-133 ° (from acetone diethyl ether); UV spectrum hydroxy-acetic acid p-nitrobenzyl ester is the title compound

646 173

26

with the following physicochemical properties: TLC: Rf = 0.23 (toluene-ethyl acetate 1: 2), IR spectrum (CH2C12): absorption bands at 2.95; 5.65; 5.75; 5.82; 6.25; 6.60; 7.45; 8.25; 9.05 and 11.75 ji.

Example 50

2-f (4R, S) -4- (4-p-nitrobenzyloxycarbonylaminobutyrylthio) -2-oxo-l-azetidinyl] -2-triphenylphosphoranylidene acetic acid p-nitrobenzyl ester.

a) To a mixture of 3.676 (, 6.38 mM) 2 - [(4R, S) -4- (4-p-nitrobenzyloxycarbonylaminobutyrylthio) - 2 -oxo-

1-azetidinyl] - 2-hydroxyacetic acid p-nitrobenzyl ester and 8 g of poly-Hunig base in 50 ml of absolute dioxane, a solution of 4 ml of thionyl chloride in 25 ml of absolute dioxane is added dropwise at room temperature. The reaction mixture is stirred for 3 hours at room temperature and under nitrogen, the poly Hunig base is filtered off and the filtrate is evaporated in vacuo.

b) The crude -2- [(4R, S) -4- (4-p-nitrobenzyloxy-carbonylaminobutyrylthio) -2-oxo-l-azetidinyl] - 2-chloroacetic acid-p-nitrobenzyl ester obtained in 100 ml of absolute Dissolved dioxane, mixed with 9 g of poly Hunig base and 3 g of triphenylphosphine and stirred overnight at 50 ° under nitrogen. The poly-Hunig base is filtered off and the filtrate is evaporated in vacuo. The residue is chromatographed on silica gel with toluene-ethyl acetate 9: 1.8: 2 and 1: 1 and gives the title compound with the following physico-chemical properties: IR spectrum (CH2C12): absorption bands at 5.70; 5.80; 5.95; 6.25; 6.60; 7.00; 7.45; 8.15; 8.95; 9.05 and 9.25 h.

Example 51

(5R, S) -2- (3-p-nitrobenzyloxycarbonylaminopropyl) -

2-penem-3-carboxylic acid p-nitrobenzyl ester.

A solution of 1.50 g (1.83 mM) 2 - [(4R, S) -4- (4-p-Ni-trobenzyloxycarbonylaminobutyrylthio) - 2-oxo-l-azetidin-yl] - 2-triphenylphosphoranylidene acetic acid p-nitrobenzyl ester in 500 ml of dry toluene is mixed with a catalytic amount of hydroquinone and stirred under nitrogen at 90 ° for 24 hours. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel with toluene-ethyl acetate 4: 1. The title compound is obtained with the following physicochemical properties: TLC: Rf = 0.43 (toluene-ethyl acetate 1: 2); UV spectrum (ethanol) A.max = 300 nm; 264 nm; IR spectrum (CH2C12): absorption bands at 2.80; 5.55; 5.80; 6.20; 6.37; 6.55; 7.40; 7.60 and 8.35 p .; NMR spectrum (in CDC13 / 100 Mc; in ppm): 1.80, quintet, J = 7Hz, 2H, m, 2H; 3.24, qu, J = 7Hz, 2H; 3.47, dd, J, = 16Hz, J2 = 2Hz, 1H; 3.82, dd, J, = 16Hz, J2 = 4Hz, 5.17, s, 2H; 5.18, d, J = 14Hz, 1H. 5.43, d, J = 14Hz, 1H; 5.64, qu, J, = 2Hz, J2 = 4Hz, 1H; 5.10-5.70, b, 1H; 7.40-8.20, m,

8H.

Example 52

(5R, S) -2 - (3-aminopropyl) -2-penem-3-carboxylic acid.

A solution of 30 mg (0.055 mM) (5R, S) - 2 - (3-p-nitro-benzyloxycarbonylaminopropyl) - 2-penem-3-carboxylic acid p-nitrobenzyl ester in 3 ml of methanol is mixed with 80 mg of 10% palladium / Carbon catalyst added and stirred at normal pressure for 11 ji hours under hydrogen. The hydrogenation mixture is filtered off from the catalyst via diatomaceous earth and the filtrate is evaporated in vacuo. The title compound obtained has the following physicochemical properties: IR spectrum (KBr): absorption bands at 2.95; 3.45; 5.65; 5.85 sh; 6.35 and 7.30 jx; UV spectrum (ethanol): Ä-inax = 299 nm.

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Example 53

(4R, S) -3- (4-p-nitrobenzyloxycarbonylaminopropionyl-thio) -2-oxo-azetidine.

A precooled solution of 2.2 g (17 mM) (4R, S) -4-acetoxyazetidin-2-one in 10 ml dioxane is added dropwise with a cold prepared solution of 5.60 g (~ 20 mM) 3- p-Nitrobenzylcarbonylamino-thiopropionic acid in 20 ml IN sodium hydroxide solution and stirred at room temperature for 3 hours. The reaction mixture is extracted exhaustively with methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel with toluene-ethyl acetate 9: 1 to 1: 1 and gives the title compound with the following physicochemical properties. TLC: Rf = 0.22 (toluene-ethyl acetate 1: 1); IR spectrum (CH2C12): absorption bands at 2.95; 5.65; 5.80; 5.95; 6.60; 7.45 and 8.17 h.

The thiocarboxylic acid used as the starting material is obtained as follows:

a) A solution of 8.90 g (0.1 mM) of 3-aminopropionic acid in 100 ml of 2N sodium hydroxide solution in an ice bath is added dropwise within 20 minutes with a solution of 21.56 g (0.1 mM) of p-nitrobenzyl -chloroformatin 30 ml dry dioxane added. The reaction mixture is stirred for 2 hours at room temperature and acidified with 2N hydrochloric acid. The precipitated 3-p-nitrobenzyloxycarbonylaminopropionic acid is filtered off and dried. Melting point: 97-98 ° (from ethyl acetate / diethyl ether).

b) To a solution of 5.36 g (20 mM) of 3-p-nitrobenzyloxycarbonylaminopropionic acid in 100 ml of dry methylene chloride, cooled to −10 °, 4.4 g (40 mM) of triethylamine and a solution of 2.8 ml (2nd mM) drop of isobutyl chloroformate in 20 ml of dry methylene chloride. The reaction mixture is at one hour

Stirred at -18 °, then a strong stream of hydrogen sulfide was passed through for 1/2 hours and allowed to warm to room temperature. After acidification with 2N sulfuric acid, again in the cold, the organic phase is separated off, dried and evaporated in vacuo. The 3-p-nitrobenzyloxycarbonylamino-thiopropionic acid obtained can be processed further without further purification.

Example 54

2- [(4R, S) -4- (3-p-nitrobenzyloxycarbonylaminoprop-45 ionylthio) -2-oxo-l-azetidinyl] - 2-hydroxyacetic acid p-nitrobenzyl ester.

At room temperature 4.10 g (11.6 mM) (4R, S) -4- (3-p-nitrobenzyloxycarbonylaminopropionylthio) - 2-oxo-azetidine and 6.5 g of 2-ethoxy-2-hydroxy-acetic acid-p -nitro-benzyl ester dissolved in 120 ml of dry toluene and 50 ml of dry dimethylformamide. After adding freshly dried molecular sieves, the mixture is stirred under nitrogen overnight at room temperature and then at 50 ° for 2 hours. The molecular sieves are filtered off, the filtrate is evaporated in vacuo and the residue is chromatographed on silica gel with toluene-ethyl acetate 9: 1 to 1: 1. After elution of unreacted p-nitrobenzyl 2-ethoxy-2-hydroxyacetic acid, the title compound is eluted with the following physicochemical properties: TLC: Rf = 0.23 (toluene-ethyl acetate 1: 1); IR spectrum (CH2C12): absorption bands at 2.95; 5.65; 5.75; 5.80; 6.25; 6.55; 7.45; 8.20 and 9.20 \ i.

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Example 55

2- [(4 R, S) -4- (3-p-nitrobenzyloxycarbonylaminoprop-ionylthio) -2-oxo-l-azetidinyl] - 2-triphenylphosphoranylidene-acetic acid-p-nitrobenzyl ester.

27 646173

a) To a stirred mixture of 6.33 g (11.2 mM) The residue is chromatographed on silica gel with toluene-ethyl acetate 1: 1 2 - [(4R, S) -4- (3-p-nitrobenzyloxycarbonylaminopropionyl) and gives the Title compound with the thio) - 2 -oxo-1 -azetidinyl] - 2 -hydroacetic acid-p-nitrobenzyl- following physicochemical properties. TLC: Rf = 0.38 ester and 12 g poly-Hunig base in 50 ml dry dioxane (toluene-ethyl acetate 1: 2); IR spectrum (CH2C12): A solution of 6 ml of thionyl chloride bands at 2.95 is absorbed at room temperature; 5.60; 5.80; 5.90; 6.60 and 8.10

dripped into 50 ml of dry dioxane. The reaction mixture The thiocarboxylic acid mixture used as the starting material is obtained for 1 hour at room temperature and under stick conditions as follows:

Stuffed material, the poly-Hunig base is filtered off and the fil- a) A solution of 10.60 g (0.1 mM) 4-aminobutter was evaporated in vacuo. acid is dissolved in 300 ml IN sodium hydroxide solution in a b) The crude 2 - [(4R, S) -4- (3-p-nitrobenzyloxy- io ice bath obtained dropwise within 30 minutes with a solution of carbonylaminopropionylthio) -2-oxo-1 - azetidinyl] - 2-chloro- of 5.16 g (0.103 mM) benzyl chloroformate in 100 ml dry p-nitrobenzyl acetate is added in 50 ml dry dioxane and dioxane. The reaction mixture is dissolved for 30 minutes, stirred with 12 g of poly-Hunig base and 4 g of triphenylphosphine at room temperature, acidified with 2N hydrochloric acid and stirred overnight at 50 ° under nitrogen. The ert and extracted with methylene chloride. The organic phase poly-Hunig base is filtered off and the filtrate in vacuum 15 is dried with sodium sulfate and evaporated in vacuo. The residue is evaporated on silica gel with toluene. The 4-benzyloxycarbonylamino-butter-ethyl acetate 9: 1.8: 2 and 1: 1 obtained is chromatographed and gives the acid is crystallized from ethyl acetate, methylene chloride and hexane um title compound with the following physico-chemical egg; Melting point 61-62 °.

properties: IR spectrum (CH2C12): absorption bands at b) to a solution of 2.37 g (10 2.90; 4.67; 5.77; 5.90; 6.12; 6.55; 6.95; 7.40; 9.00 and 9.25 ji. 20 mM) 4-benzyloxycarbonylaminobutyric acid in 50 ml dry methylene chloride 2.2 g (20 mM) Example 56 triethylamine and a solution of 1.4 ml ( 10 mM) isobutene

(5R.SJ-2- (2-p-nitrobenzyloxycarbonylaminoethyl) - yl chloroformate in 20 ml dry methylene chloride, added 2-penem-3-carboxylic acid p-nitrobenzyl ester. The reaction mixture is stirred for one hour at -10 °

A solution of 3 g (3.7 mM) 2 - [(4R, S) -4- (3-p-nitro- 25) is stirred and then a strong benzyloxycarbonylaminopropionylthio) - 2 -oxo-1 - azetidine is stirred for 11/2 hours - Passed hydrogen sulfide stream. After warming to yl) - 2 -triphenylphosphoranyliden-acetic acid-p-nitrobenzyl- room temperature is cooled again and acidified with a 2N ester in 250 ml of dry toluene with a catalytic sulfuric acid. The organic phase is mixed with a quantity of hydroquinone and separated under nitrogen for 24 hours, dried and evaporated in vacuo. The get stirred at 90 °. The solvent which has been removed in vacuo, 4-benzyloxycarbonylamino-thiobutyric acid can be evaporated without and the residue can be further processed on silica gel with toluene ether.

Chromatographed 9: 1 to 4: 1 ylacetate. The title compound is obtained with the following physicochemical properties: Example 59 TLC: Rf = 0.44 (toluene-ethyl acetate 1: 1); UV spectrum (Di-2-f (4R, S) -4 (4-benzyloxycarbonylaminobutyrylthio) -2-oxane): A max = 315 nm (e = 8536); 264 nm (e = 22 114); IR-35 oxo-l-azetidinyl] - 2-hydroxyacetic acid p-nitrobenzyl ester. Spectrum (CH2C12): absorption bands at 2.95; 5.58; 5.80; At room temperature, 2.60 g (8 mM) (4R, S) -4- (4-6.22; 6.32; 6.57; 7.42; 7.62 and 8.35 h; NMR spectrum (in benzyloxycarbonylaminobutyrylthio) - 2-oxo-azetidine and CDCI3 / IOO Mc; in ppm): 2.80-3.60, m, 5H; 3.84, dd, 4.84 g p-nitrobenzyl ester of 2-ethoxy-2-hydroxyacetic acid in J] = 16Hz, J2 = 4Hz, 1H; 5.18, s, 2H; 5.22, d, J! = 14Hz, 1H; a mixture of 100 ml of dry toluene and 3 5 ml of trok-5.44, d, J = 14Hz; 1H; 5.65, qu, J2 = 4Hz; J3 = 2Hz, 1H; 7.40-40 kenem dimethylformamide dissolved. After adding fresh 8.30, m, 8H. dried molecular sieves, the mixture is under

Nitrogen stirred overnight at room temperature and then Example 57 for 2 hours at 50 °. The molecular sieves are

(5R, S) -2- (2-aminoethyl) -2 -penem-3-carboxylic acid. the filtered off, the filtrate is evaporated in vacuo and

A solution of 90 mg (0.19 mM) (5R, S) - 2 - (2-p-nitro- 45 the residue on silica gel with toluene-ethyl acetate 4: 1 chro-benzyloxycarbonylaminoethyl) - 2 -penem-3-carboxylic acid - matographed. After elution of unreacted 2-eth-p-nitrobenzyl ester in 3 ml of methanol, the title is extracted with 200 mg of oxy-2-hydroxy-acetic acid p-nitrobenzyl ester.

10% palladium / carbon catalyst was added and, with Nor compound, the following physico-chemical pressure was stirred for one hour under hydrogen. shaft eluted: TLC: Rf = 0.38 (toluene-ethyl acetate 1: 2); IR-The hydrogenation mixture is over catalytic diatomaceous earth 5 spectrum (CH2C12): absorption bands at 2.85.2.95; 5.60; filtered off, the filtrate evaporated in vacuo and the 5.70; 5.82; 5.97; 6.22; 6.55; 7.42; 8.25; 9.15 yes.

Residue washed once with diethyl ether. The received

The title compound has the following physicochemical properties - Example 60

ten: IR spectrum (KBr): absorption bands at 3.00; 5.67; 2 - [(4R, S) -4- (4-benzyloxycarbonylaminobutyrylthio) -2-

5.90; 6.25; 6.30 and 7.30 n. 55 oxo-l-azetidinyl] -2- triphenylphosphoranylidene-vinegar-

acid p-nitrobenzyl ester.

Example 58 a) To a mixture of 7 g of 2 - [(4R, S) -4- (4-benzyloxy-

(4R, S) -4- (4-benzyloxycarbonylamino-butyrylthio) - carbonylaminobutyrylthio) - 2 - oxo-1-azetidinyl] - 2 - hydr-

2-oxoazetidine. oxyacetic acid p-nitrobenzyl ester and 15g poly Hunig base in

A solution of 1.29 g (10 mM) (4R, S) -4-acetoxyaceti- 60 200 ml of dioxane becomes a solution of 6 din- 2 -one in 10 ml of dioxane at room temperature is added dropwise with one in ml of thionyl chloride Dropped 50 ml of dioxane. The reaction cold prepared solution of 2.53 g (10 mM) 4-benzyloxycar mixture is stirred for 2 hours at room temperature, the bonylamino-thiobutyric acid in 10 ml IN sodium hydroxide poly-Hunig base is filtered off and the filtrate is added in a vacuum solution and stirred at room temperature for 20 minutes. ^ evaporated.

The reaction mixture is exhaustively extracted with methylene chloride. B) The crude 2 - [(4R, S) -3- (4-benzyloxycarbonyl-rid obtained) is extracted. The combined organic phases are aminobutyrylthio) - 2 - oxo-1-azetidinyl] - 2 - chloroacetic acid-dried over sodium sulfate and evaporated in vacuo, re-p-nitrobenzyl ester is dissolved in 150 ml dry dioxane

646 173

28

dissolves, mixed with 15 g of poly Hunig base and 6 g of triphenylphosphine and stirred overnight at 50 °. The poly-Hunig base is filtered off and the filtrate is evaporated in vacuo. The residue is chromatographed on silica gel with toluene-ethyl acetate 9: 1 to 1: 1 and gives the title compound with the following physico-chemical properties: TLC: Rf = 0.37 (toluene-ethyl acetate 1: 2); IR spectrum (CH2C12): absorption bands at 2.92.5.70; 5.78; 5.92; 6.15; 6.60; 6.97; 7.45; 8.40; 8.95; 9.05 and 9.251i.

Example 61

(5R, S) -2- (3-Benzyloxycarbonylaminopropyl) -2-pen-em-3-carboxylic acid p-nitrobenzyl ester.

A solution of 1 g (1.29 mM) 2 - [(4R, S) -4- (4-benzyl-oxycarbonylaminobutyrylthio) - 2-oxo-l-azetidinyl] - 2-triphenylphosphoranylideneacetic acid-p-nitrobenzyl ester in 500 ml dry toluene a catalytic amount of hydroquinone is added and the mixture is stirred under nitrogen at 90 ° for 36 hours. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel with toluene-ethyl acetate 4: 1. The title compound is obtained with the following physicochemical properties: TLC: Rf = 0.42 (toluene-ethyl acetate 1: 1); UV spectrum (ethanol): Xmax = 311 nm; 260 nm; IR spectrum (CH2C12): absorption bands at 2.95; 5.60; 5.85; 6.20; 7.45; 7.65; 8.10 and 8.38 p .; Nuclear Magnetic Resonance Spectrum (in CDCI3 / 100 Mc; in ppm): 1.75, quintet, 2H; 2.85; m 2H; 3.19, qu, J = 7Hz, 2H; 3.40, dd; J, = 16Hz, J2 = 2Hz, 1H; 3.74, dd, J, = 16Hz, J2 = 4Hz, 1H; 5.06, s, 2H; 5.14, d, J = 14Hz and 5.38, d, J = 14Hz, 2H; 5.60, qu,

Jj = 2Hz, J2 = 4Hz, 1H; 7.28, s, 5H; 7.54, d, J = 9Hz, 2H; 8.12, d, J = 9Hz, 2H.

Example 62

(5R, S) -2- (3-benzyloxycarbonylaminopropyl) - 2-pen-em-3-carboxylic acid.

A solution of 105 mg (0.21 mM) (5R, S) - 2 - (3-Benzyloxycarbonylaminopropyl) - 2 - penem-3-carboxylic acid p-nitrobenzyl ester in 6 ml of ethyl acetate and 4 ml of 0.2 M sodium hydrogen carbonate solution 200 mg of 10% palladium / carbon catalyst are added and the mixture is stirred under atmospheric pressure for one hour under hydrogen. The hydrogenation mixture is filtered off from the catalyst over diatomaceous earth, the aqueous phase is separated off, acidified with 5% citric acid solution and extracted with methylene chloride. The organic phase is dried over sodium sulfate and evaporated in vacuo. The title compound obtained has the following physicochemical properties: TLC: Rf = 0.41 (toluene-ethyl acetate-acetic acid 60: 40: 5); IR spectrum (CH2C12). Absorption bands at 2.95; 5.60; 5,85,6,40; 6.65 and 8.10 p; UV spectrum (ethanol): Xmax - 307 and 255 nm.

Example 63

(4R, S) -4- [2- (2-phenoxyacetylamino) acetylthio] -2-oxoacetidine.

A precooled solution of 3.43 g (26.5 mM) (4R, S) -4-acetoxyazetidin - 2 - one in 20 ml of dioxane is added dropwise with a cold solution of 6 g (26.6 mM) 2 - (2-Phenoxyacetylamino) thioacetic acid in 26 ml IN sodium hydroxide solution and stirred at room temperature for 30 minutes. The reaction mixture is extracted exhaustively with methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel with toluene-ethyl acetate 1: 1 and gives the title compound with the following physicochemical properties. Melting point: 114-115 ° (from methylene chloride / petroleum ether); TLC: Rf = 0.41 (ethyl acetate); IR spectrum

(CH2C12): absorption bands at 2.95; 5.60; 5.90; 6.25; 6.60; 6.70; 8.10; 9.25; 9.42; 10.20 p.

The thiocarboxylic acid used as the starting material is obtained as follows.

s To a solution cooled to -10 ° of 5.63 g (26.9 mM) of 2- (2-phenoxyacetylamino) acetic acid in 50 ml of dry methylene chloride, 7.4 ml (53.8 mM) of triethylamine and a solution of 3.7 ml (26.9 mM) of isobutyl chloroformate in 60 ml of methylene chloride was added dropwise. The reaction mixture is stirred for 11 hours at -10 ° and a stream of hydrogen sulfide is passed through for 2 hours at the same temperature. After warming to room temperature, the mixture is acidified with 2N sulfuric acid, the organic phase is separated off, dried and evaporated in vacuo. 15 The 2- (2-phenoxyacetylamino) acetic acid obtained can be processed without further purification.

Example 64

2 - [(4R.S) -4- [2- (2-Phenoxyacetylamino) acetylthio] -20 2-oxo-l-azetidinyl -2-hydroxyacetic acid p-nitrobenzyl ester.

At room temperature, 1.40 g (4.76 mM) (4R, S) -4- [2- (2-phenoxyacetylamino) acetylthio] - 2 - oxo-azetidine and 3.2 g 2-ethoxy - 2 - hydroxy p-nitrobenzyl acetate dissolved in a mixture of 60 ml of toluene and 15 ml of dimethylform-25 amide. After adding freshly dried molecular sieves, the mixture is stirred under nitrogen overnight at room temperature and then at 50 ° for 2 hours. The molecular sieves are filtered off, the filtrate is evaporated in vacuo and the residue is chromatographed on silica gel with toluene / ethyl acetate 1: 2. After elution of unreacted 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester, the title compound is eluted with the following physicochemical properties: TLC: Rf = 0.43 (ethyl acetate); IR spectrum (CH2C12): absorption bands 35 at 2.95; 5.60; 5.70; 5.90; 6.25; 6.55; 7.42; 8.20 p.

Example 65

2 - {(4R, S) -4- [2- (2-phenoxyacetylamino) acetylthio) -2-oxo-1-azetidinyl} - 2 - triphenylphosphoranylidene-acetic acid-p-nitrobenzyl ester.

a) To a mixture of 3.01 g (5.88 mM) 2 - {(4R, S) -4- [2- (2-phenoxyacetylamino) acetylthio] - 2 - oxo-l-azetidinyl} - 2 - p -nitrobenzyl ester of hydroxyacetic acid and 4.45 g of poly Hunig base in 65 ml of dry dioxane, a solution of 0.76 ml of thionyl chloride in 25 ml of dioxane is added dropwise at room temperature. The reaction mixture is stirred for 2 hours at room temperature and under nitrogen, the poly Hunig base is filtered off and the filtrate is evaporated in vacuo.

b) The crude 2 - {(4R, S) -4- [2- (2-phenoxyacetylamino) acetylthio] - 2 - oxo-l-azetidinyl - 2 - chloroacetic acid p-nitrobenzyl ester obtained is dissolved in 100 ml of dioxane dissolved, mixed with 5.62 g of poly Hunig base and 2.30 g of triphenylphosphine and

55 stirred for 17 hours at 50 ° under nitrogen. The poly-Hunig base is filtered off and the filtrate is evaporated in vacuo. The residue is chromatographed on silica gel with toluene-ethyl acetate 3: 2 and gives the title compound with the following physico-chemical properties: TLC: Rf = 0.09 (toluene-ethyl acetate 1: 1); IR spectrum (CH2C12): absorption bands at 2.95; 5.70; 5.80; 6.20; 6.70; 6.98; 7.45; 8.40; 8.95 h.

Example 66

(5 R, S) - 2 - (2-phenoxyacetylaminomethyl) - 2 -penem-3-carboxylic acid p-nitrobenzyl ester.

A solution of 600 mg (0.8 mM) 2 - {(4R, S) -4- [2- (2-phenoxyacetylamino) acetylthio] - 2 -oxo-l-azetidinyl {- 2 -tri-

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646 173

phenylphosphoranylidene-acetic acid-p-nitrobenzyl ester in 300 ml of dry toluene is mixed with a catalytic amount of hydroquinone and stirred under nitrogen at 90 ° for 17 hours. The solvent is evaporated in vacuo, the residue is dissolved in methylene chloride and washed with cold IN sodium hydroxide solution. The organic phase is dried over sodium sulfate and evaporated in vacuo.

The residue is chromatographed on silica gel with toluene-ethyl acetate 4: 1. The title compound is obtained with the following physicochemical properties: Melting point: 163-165 ° (methylene chloride / petroleum ether); TLC: Rf = 0.35 (toluene-ethyl acetate 1: 1); UV spectrum (dioxane): Ä, roax = 318 nm (s = 10 019); 272 nm (sh) (s = 12,684), 266 nm (s = 14,869); 261 nm (e = 14 869): IR spectrum (CH2C12): absorption bands at 2.95; 5.55; 5.85; 5.90; 6.30; 6.55; 6.70; 7.40; 7.60; 8.10; 8.25; 8.65; 9.40 h; NMR spectrum (in CDC13 / 100 Mc; in ppm: 3.44, dd, Jj = 16Hz; J2 = 2Hz, 1H; 3.84, dd, J, = 16Hz, J3 = 4Hz, 1H; 4.52, s, 2H; 4.34-4.80, m, 2H; 5.22, d, J = 14Hz, 1H; 5.44, d, J = 14Hz, 1H; 4.66, qu, J2 = 2Hz, J3 = 4Hz, 1H; 6.80-8.30, m, 10H.

Example 67

(5R, S) - 2- (2-phenoxyacetylaminomethyl) -2 -penem-3-carboxylic acid.

A solution of 100 mg (0.21 mM) (5R, S) - 2 - (2-phen-oxyacetylaminomethyl) - 2 -penem-3-carboxylic acid-p-nitro-benzyl ester in 10 ml of ethyl acetate and 2.7 ml 0.2 N sodium hydrogen carbonate solution is mixed with 135 mg of 10% palladium / carbon catalyst and stirred under normal pressure for 45 minutes under hydrogen. The hydrogenation mixture is filtered off from the catalyst via diatomaceous earth. The aqueous phase is separated off, acidified with 5% citric acid solution and extracted with methylene chloride. The combined methylene chloride phases are dried over sodium sulfate and evaporated in vacuo. The title compound obtained has the following physicochemical properties: TLC: Rf = 0.08 (toluene-ethyl acetate-acetic acid 60: 40: 5); IR spectrum (methylene chloride): absorption bands at 2.8-3.60 b; 5.55; 5.75; 5.85; 6.25; 6.55; 6.70 and 8.10 | i.

Example 68

(4R, S) -4-ethylthio-thiocarbonylthio-2-oxo-azetidine.

A solution of 1.32 g (4R, S) -4-acetoxy-azetidin-2-one in 3.5 ml of water and 1 ml of acetone is added dropwise at room temperature under a nitrogen atmosphere with a solution of 2.25 g of potassium ethyl trithiocarbonate in 12 ml Water is added and the mixture is stirred at the same temperature for 30 minutes. The reaction mixture is extracted exhaustively with methylene chloride, the combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue is recrystallized from diethyl ether and gives the title compound in the form of yellow needles. Melting point: 99.5-101.5 °; TLC: Rf = 0.315 (toluene-ethyl acetate 2: 3); IR spectrum (CH2C12): absorption bands at 2.95; 5.6; 8.12; 9.15; 9.3 \ i. NMR spectrum (in CDC13 / 100 Mc; in ppm): 6.85.1H, m (exchange with D20) 5.55.1H, m; 3.35.2H, q; 3.6-2.9.2H, m; 1.35, 3H, t.

Example 69

2- [(4R, S) -4-ethylthiothiocarbonylthio-2-oxo-1-azetidinyl J-2-hydroxy-acetic acid p-nitrobenzyl ester.

At room temperature, a solution of 621 mg (3 mM) (4R, S) -4-ethylthiothiocarbonylthio-3-oxo-azetidine in 35 ml of toluene and 9 ml of dimethylformamide with 1.7 g of 2-ethoxy-2-hydroxy-acetic acid. p-nitrobenzyl ester added. To

Addition of freshly dried molecular sieves, the mixture is stirred under nitrogen for 15 hours at room temperature and then for 2 hours at 50 °. The molecular sieves are filtered off, washed with toluene and the filtrate and washing liquid are evaporated together in vacuo. The residue is dried under high vacuum and chromatographed on 80 g silica gel with toluene-ethyl acetate 9: 1. The title compound is obtained with the following physicochemical properties: TLC: Rf = 0.26 (toluene-10 ethyl acetate 2: 3); IR spectrum (CH2C12): absorption bands at 5.62; 5.7; 6.55; 7.45 \ i. Nuclear Magnetic Resonance Spectrum (in CDC13 / 100 Mc, in ppm): 8.3-8.15.25H, m; 7.6-7.45.2H, m; 6.1-5.9.1H, m; 5.55; 1H, d; 5.4-5.3.2H, m; 4.2-4.1H, m (exchange with D20); 3.8-3.4H, m; 1.35.3H, t.

15

Example 70

2- (4R, S) - [(4-Àthylthiothiocarbonylthio-2-oxo-l-azetidynyl) - 2 -triphenylphosphoranylidene-acetic acid-p-nitrobenzyl ester.

20 a) A solution of 1.1 g of 2 - [(4R, S) -ethylthiothiocarbon-ylthio-2-oxo-l-azetidinyl) - 2-hydroxyacetic acid-p-nitro-benzyl ester in 23 ml of absolute dioxane becomes 30 already Minutes of stirred solution of 4.55 g of poly Hunig base in 11 ml of absolute dioxane. After adding dropwise a solution of 0.8 ml of thionyl chloride, the reaction mixture is stirred for 3 hours at room temperature and under nitrogen. The poly-Hunig base is filtered off, washed with dioxane and the filtrate is evaporated in vacuo. The crude 2 - [(4R, S) -4-ethylthiothiocarbonylthio-2-30 oxo-l-azetidinyl) -2-chloroacetic acid p-nitrobenzyl ester obtained can be used in the next step without further purification.

b) The crude 2 - [(4R, S) -4-ethylthiothiocarbonyI-thio-2-oxo-l-azetidinyl) - 2-chloroacetic acid p-nitrobenzyl ester obtained is dissolved in 54 ml of absolute dioxane, with 4.55 g of poly Hunig base and then mixed with 1.42 triphenylphosphine and stirred for 15 hours at 50 ° under nitrogen. The poly-Hunig base is filtered off, washed with dioxane and the filtrate and washing liquid are evaporated together in vacuo. The residue is chromatographed on 60 g of silica gel with toluene-ethyl acetate 7: 3 and gives the title compound with the following physicochemical properties: TLC: Rf = 0.43 (toluene-ethyl acetate 2: 3); IR spectrum (CH2C12): absorption bands at 5.67; 6.15; 6.57; 6.97; 7.43; 9.05 p.

Example 71

(5R, S) - 2-ethylthio- 2 -penem-3-carboxylic acid-p-nitrobenzyl ester.

A solution of 9.8 (14.85 mM) 2- [4R, S) -4-ethylthio-thiocarbonylthio-2-oxo-l-azetidinyl] -2-triphenylphos-phoranylidene-acetic acid-p-nitrobenzyl ester in 31 dry o -Xylene is stirred under nitrogen for 10 hours under reflux. The solvent is evaporated in vacuo and the residue is chromatographed on 400 g of silica gel with toluene-ethyl acetate 19: 1 and then 9: 1. The title compound is obtained after crystallization from diethyl ether-methylene chloride in the form of colorless crystals; Melting point: 133-134 ° C; TLC: Rf = 0.69 (toluene-ethyl acetate 2: 3): IR spectrum (CH2C12): absorption bands at 5.57; 5.9; 6.22; 6.55; 6.65; 7.42; 7.55; 8.37; 9.0; 9.7 | x. Nuclear Magnetic Resonance Spectrum (in CDC13 / 100 Mc: in ppm): 8.25-8.15.25H, m; 7.65-7.55.2H, m; 5.7.1H, 5.32.2H, m (AB); 3.9-3.4.2H, m; 3.1-2.8.2H, m; 2.3-1.5.3H, t. The reaction reaction can also be carried out in boiling toluene, although the reaction time is extended to 120 hours. If desired, a catalytic amount of hydroquinone can be added to the reaction solution.

35

40

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55

60

65

646 173 30

Example 72 ester is recrystallized from methylene chloride diethyl ether.

(5R, S) -2-ethylthio-2-penem-3-carboxylic acid. Melting point: 121-123 °.

A solution of 1 g (2.73 mM) (5R, S) - 2-ethylthio-2 b) A solution of 22.8 g of fumaric acid diacetonylester in -penem-3-carboxylic acid p-nitrobenzyl ester in 70 ml of absolute 400 ml of methylene chloride and 200 ml of methanol is ozonized at -15 ° ethyl acetate with 40 ml of 0.2 M aqueous sodium hydro- 5 for about 9 hours until no starting material carbonate solution and 2 g of 10% palladium / carbon catalyst can be detected. The ozonizing mixture is mixed with lyser and 100 ml of dimethyl sulfide are added at normal pressure for 50 minutes and the mixture is stirred overnight at room temperature under hydrogen. The hydrogenation mixture is left to stand above temperature. Evaporation of the solvents in the diatomaceous earth is filtered off from the catalyst, with 0.2 N sodium vacuum and distillation of the residue at 70-80 ° / 0.05 um hydrogen carbonate solution and several times with 10 mm Hg ethyl acetate gives the glyoxylic acid acetonylester. did washed. The aqueous phase is washed with methylene chloride, acidified with 5% aqueous citric acid solution and, with methylene chloride, exhaustively extra-2-f (4R, S) -4-cis- 2-carbomethoxyvinylthio) -2-oxo-1-hydrogenated . The combined organic phases are acetylated over natrazetidinyl] - 2-chloroacetic acid.

Desulphate dried, filtered ^ evaporated in vacuo and 15 A solution of 1.7 g 2 - [(4R, S) -4- (cis-

dried in a high vacuum. The title compound obtained 2-carbomethoxyvinylthio) - 2-oxo-1-azetidinyl] - 2 -hydroxy-

has the following physicochemical properties: Melt acetic acid acetonylester in 25 ml dry tetrahydrofuran point: 143-145 ° (from diethyl ether acetone) TLC: Rf = 0.27 is stirred with 0.43 ml (6 mM) thionyl chloride and

(Toluene-ethyl acetate-acetic acid 60: 40: 5); IR spectrum then within 5 minutes with a solution of 0.83

(KBr): absorption bands at 3.6-3.3; 5.6; 6.0; 6.75; 6.97; 20 ml (6 mM) triethylamine in 2 ml dry tetrahydrofuran

7.5; 7.9; 8.15; 8.8 | i; NMR spectrum (DMSO d6 / 100 Mc; added. The reaction mixture is stirred for 15 minutes at 0 °

ppm): 5.75.1H, m; 4-3,3,2H, m; 3.1-2.8.2H, m; 1.4-1.2, stirred, 150 ml of cold methylene chloride and

3H, t. washed with hydrochloric acid ice water. The organic phase is dried over sodium sulfate and concentrated in vacuo.

Example 73 25 is steaming. The residue is dissolved in 60 g of silica gel with toluene

(4R, S) -4- (eis-2-carbomethoxyvinylthio) -azetidine-2 -one. Ethyl acetate 1: 1 chromatographed and gives the title compound

To a solution of 206 manure cooled to - 15 ° to - 10 °. IR spectrum (in CH2C12): absorption bands at 5.6;

mg (1.05 mM) ice-2-carbomethoxyvinyl-isothiuronium-hy-5.75; 5.85; 7.3; 8.15; 8.5 | i.

drochloride (E.G. Kako et al., J. Org. Chem. USSR, 1969,

610, Engl. Output) in 2 ml of methanol slowly become 2 ml of 30 Example 76

precooled IN aqueous sodium hydroxide solution and 2 - [(4R, S) -4- (cis- 2-carbomethoxyvinylthio) - 2-oxo-1-closing at about -12 ° 130 mg (1 mM) (4R, S) - 4-acetoxyacetidinyl] - 2-triphenylphosphoranylidene-acetic acid-acetonyl-

Azetidin-2 -one dissolved and 1 ml of methanol added. The reactors.

tion mixture is stirred at -10 ° for 30 minutes, with water A solution of 1.15 g (3.3 mM) 2 - [(4R, S) -4- (cis- 2 -Car-

diluted, saturated with sodium chloride and with ethyl acetate-35-bomethoxyvinylthio) -3-oxo-l-azetidinyl] - 2-chloroacetic acid-

here. The combined ethyl acetate extracts are dried with sodium acetyl ester in 3 ml of dry tetrahydrofuran with sulfate and evaporated in vacuo. The 1.73 g (6.6 mM) triphenylphosphine added and at room

The residue is evaporated on silica gel with toluene-ethyl acetate 2: 1 chro-temperato for 15 hours in a nitrogen atmosphere.

matographs and delivers the title compound, which is left standing according to the environment. The reaction mixture is diluted with 50 ml of crystallization from hot benzene, melting point 92-93 ° methylene chloride, with cold, saturated aqueous. IR spectrum (in CH2C12): absorption bands washed with sodium bicarbonate solution, over sodium

5.6; 5.9; 6.3; 8.2; 8.5] i. dried sulfate and evaporated in vacuo. The residue is chromatographed on 40 g silica gel with toluene-ethyl acetate 1: 1.

Example 74 matographs and gives the title compound. IR spectrum

2 - [(4R, S) -4- (cis- 2 -carbomethoxyvinylthio) -2-oxo-1- (inCH2Cl2): absorption bands at 5.65.5.85; 6.1; 6.3 | x. azetidinyl] - 2-hydroxyacetic acid acetonylester.

A solution of 936 mg (5 mM) (4R, S) -4- (cis- 2 -carbo-Example 77

methoxyvinylthio-azetidin-2 -one in 5 ml of dry dimeth- (5R, S) -2 -penem-3-carboxylic acid acetonylester.

ylformamide and 10 ml xylene is mixed with 1.66 g (12.5 mM) Gly-5Q. A solution of 1.15 g (2 mM) 2 - [(4R, S) - (cis- 2 -carbo-

oxyacid acetonylester and 15 g well dried molecular methoxyvinylthio) - 2-oxo-l-azetidinylj- 2 -triphenyl-phos-

seven A4 were added and the phoranylidene acetic acid acetonylester was stirred in 30 ml of dry overnight at room temperature. The molecular sieves are filtered off and washed with 30 ml of methylene chloride at - 20 ° with 1 ml of trifluoroacetic acid dry tetrahydrofuran. Filtrate and washing are added, whereupon an ozone / oxygen

Liquid are evaporated together in vacuo and 5J current (0.33 mM 03 / minute) is passed through. The ozoni

the residue a few times in a vacuum of less than 0.01 solution is flushed with nitrogen, with 1.5 ml of dimethyl

mm Hg evaporated at 80 ° with xylene. The amorphous sulfide obtained was added, and after heating to room temperature

In the IR spectrum (CH2C12), the title compound has 30 ml of absorption methylene chloride and 60 ml of cold, saturated, aqueous

tied at 5.6; 5.75; 5.85; 6.8; 7.3 p. shaken sodium bicarbonate solution. The organic

The glyoxylic acid acetonylester is prepared as follows: 6Q see phase is separated, again with 20 ml of cold, sown

a) A suspension of 32 g disodium fumarate in 300 ml aqueous sodium bicarbonate solution

dry dimethylformamide is slowly seen with 3 5 ml, dried over sodium sulfate and concentrated in vacuo

Chloroacetone added and then stirred at 100 ° overnight. steams. The colorless foam containing the 2 - [(4R, S) -4-

The reaction mixture is cooled and 1.521 methylene-formylthio-2-oxo-l-azetidinyl] - 2 -triphenylphosphoranyli chloride are added and the mixture is washed with 1N hydrochloric acid and water. 65 den-acetic acid-acetonylester, is dried in a high vacuum. The organic phase is dried over sodium sulfate, in the net, in 50 ml of dry, acid-free methylene chloride.

Evaporated vacuum and refluxed in high vacuum from the rest of the rend for 30 minutes and in vacuum from

Free solvent. The fumaric acid diacetonyl solvent obtained frees. The residue is on 20 g of silica gel

31

646 173

Chromatographed 1: 1 with toluene-ethyl acetate to give the title compound. A sample recrystallized from methylene chloride diethyl ether has a melting point of 115-116 °. IR spectrum (in CH2C12): absorption bands at 5.55; 5.75 (sh); 5.8; 6.4 p; Nuclear Magnetic Resonance Spectrum (in CDC13 / 100 Mc; in ppm): 2.2.3H, s; 3.7.2H, m; 4,8,2H, s; 5.8.1H, m; 7.4.1H, s.

Example 78

(5R, S) -2 -penem-3-carboxylic acid.

A solution of 23 mg (0.1 mM) (5R, S) - 2 -penem-3-carbonic acid-acetonylester in 3 ml of tetrahydrofuran is mixed with 0 ml of 0.1 N aqueous sodium hydroxide solution at 0 ° within 30 minutes and stirred for a further 15 minutes at the same temperature door. The reaction mixture is washed with 2 ml of diethyl ether and shaken with 20 ml of methylene chloride and 0.5 ml of 20% aqueous citric acid. The organic phase is dried over sodium sulfate and evaporated in vacuo. The residue is digested with methylene chloride and the crystals are filtered off. Melting point 230 °; TLC: Rf = 0.3 (acetic acid-toluene-water 5: 5: 1); IR spectrum (in KBr): absorption bands at 5.6; 5.95; 6.45; 6.9; 12.2 p .; NMR spectrum (in DMSO d6 / 100 Mc; in ppm: 3.7.2H, m; 5.8.1H, m; 7.6.1H, s.

Example 79

(4R, S) -, (4R) -and (4S) -4- [cis- 2 -carbo- (l) -menthyl-oxyvinylthio) -aze tidin-2 -one.

2 ml IN aqueous sodium hydroxide solution and then 130 mg (1 mM) are slowly added to a solution of 321 mg (ImM) ice-2-carbo- (l) -menthyloxyvinyl-isothiuronium hydrochloride in 4 ml cooled to -10 °. (4R, S) -4-acetoxyazetidin-2-one dissolved in 2 ml of ethanol. The reaction mixture is stirred for 15 minutes at -10 ° and 15 minutes at room temperature and extracted with methylene chloride. The organic phase is dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on 10 g of silica gel with toluene-ethyl acetate 2: 1 and gives the (4R, S) title compound in crystalline form.

The pure (4S) isomer is obtained by recrystallization of the (4R, S) compound from methylene chloride-pentane at 0 °. Further amounts of this isomer can be obtained by recrystallization of the mother liquor from methanol at -70 °.

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be. Melting point 134-135 °; [a] ^ = - 82 ° ± 0.2

(c = 1%; CHC13); TLC: Rf = 0.2 (toluene-ethyl acetate 1: 1); IR

Spectrum (in CH2C12): absorption bands at 2.95; 3.4; 5.6; 5.9; 8.2; 8.5 p.

The pure (4R) - is obtained from the combined mother liquors by repeated (6 x) recrystallization from methanol at -70 ° and finally from methylene chloride-pentane at 0 °.

? 0

Obtain isomers. Melting point 139-141 °; [a] ^ = -91 ° ± 1

(c = 1%; CHCI3);

The isothiuronium salt used is prepared as follows:

a) 8 drops of concentrated sulfuric acid are added to a solution of 62.4 g (l) -methanol and 42 g propiolic acid in 120 ml benzene and the mixture is refluxed in a water separator for 21/2 days. After separation of about 9.5 ml of water, the benzene solution is diluted with 120 ml of benzene, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The pale yellow residue is chromatographed on 1 kg of silica gel with toluene-ethyl acetate 19: 1 and gives the propiolic acid- (l) -menthyl-

ester, melting point 90-92 °; [a] ^ ° = - 82 ° ± 1 ° (c = 1%; CHCI3).

A solution of 0.76 g (10 mM) of thiourea in a mixture of 5 ml of 2N hydrochloric acid and 5 ml of ethanol is slowly added to a solution of 2.04 g (10 mM) of propiolic acid (1) methyl ester in 10 ml of ethanol so that the temperature does not exceed 40 °. The reaction mixture is stirred at room temperature until it becomes clear and evaporated in vacuo 1C. The residue is washed on a glass suction filter with acetone, recrystallized from hot water and, after filtration, the crystals obtained are washed with acetone. A sample recrystallized from isopropanol of the eis-2-carbo- (l) - menthyloxyvinylisothiuronium-hy-

15 20

drochlorids has a melting point of 176-170 °; [a] ^ = -74 ° ±

1 ° (c = 1%; ethanol).

Example 80

20 (4S) - and (4R) -4- [trans- 2 -carbo- (l) -menthyl-oxyvinyl-thio] -azetidine-2 -one.

A solution of 64 mg (0.2 mM) (4S) -4- (cis-2-carbo- (l) -menthyloxyvinylthio) -azetidine-2-one in 1.5 ml octane is 90 minutes at a bath temperature of 150 ° cooked under reflux. Chromatography of the cis-trans (1: 4) isomer mixture obtained on silica gel gives the faster-running trans isomer; [a] J ^ = -159 ° ± 1 ° (c - 1%; CHC13); TLC: Rf = 04 (toluene-ethyl acetate 1: 1); IR spectrum (in 30 CH2C12): absorption bands at 2.95; 3.4; 5.6; 5.85, 6.5, 8.5 p.

In the same way, starting from (4R) -4- (cis-2-carbo- (l) -menthyloxyvinylthio) -azetidine-2-one, the (4R) -4- (trans-2-carbo- (l) - menthyloxyvinylthio-azetidin-2-one-

35 held [a] p ° = 26 ° db 1 ° (c = 1%; CHC13); DC: Rf = 0.4

(Toluene-ethyl acetate 1: 1); IR spectrum (in CHC13): absorption bands at 2.95; 3.4; 5.6; 5.85; 6.25; 8.5 p.

40 Example 81

2 - [(4S) - (cis- 2-Carbo- (1) -menthyloxyvinylthio) -2oxo-l-azetidinyl] - 2-hydroxyacetic acid acetonylester.

A mixture of 935 mg (3 mM) (4S) -4- (cis- 2 -carbo- (l) -menthyloxyvinylthio) -azetidine-2-one and 1 g (7.5 mM) 45 glyoxylic acid acetonylester in 3 ml Dry dimethylformamide and 6 ml of toluene are mixed with 12 g of molecular sieves A4 and stirred overnight at room temperature. The molecular sieves are filtered off, washed with dry tetrahydrofuran and the filtrate and washing liquid are evaporated together in vacuo and dried under high vacuum at 70 °. The residue is evaporated several times in vacuo with xylene and used in the next reaction without further purification. IR spectrum (in CH2C12): absorption bands at 5.6; 5.75; 5.9; 6.3; 8.15; 8.5 p ..

55

Example 82

2- [(4R) - (eis-2-carbo- (1) -menthyloxyvinylthio) ^ oxo-l-azetidinyl] - 2-hydroxyacetic acid acetonylester.

Analogously to Example 81, starting from (4R) -4- (cis-2-60 carbo- (l) -menthyloxyvinylthio) -azetidine-2-one, the (4R) isomer is obtained. IR spectrum (in CH2C12): absorption bands at 5.6; 5.75; 5.9; 6.3; 8.15; 8.5 p.

Example 83

65 2-1 '(4S) - (trans-2-carbo- (l) -menthyloxyvinylthio-2-oxo-l-azetidinyl] - 2-hydroxyacetic acid-acetonylester.

Analogously to Example 81, starting from (4S) -4- (trans-2-carbo- (l) -menthyloxyvinylthio) -azetidine-2-one, the (4S) -

646173

trans isomers produced. IR spectrum: same absorption bands as in example 82.

Example 84

2- [(4R) - (trans-2-carbo- (1) -menthyloxyvinylthio) -2-oxo-l-azetidinyl] - 2-hydroxyacetic acid acetonylester.

Analogously to Example 81, starting with (4R) -4- (trans-2-carbo- (l) -mentyhloxyvinylthio) -azetidinone, the (4R) -trans isomer is prepared. IR spectrum: same absorption bands as in example 82.

Example 85

2- [(4S) -4- (eis-2-Carbo- (1) -menthyloxyvinylthio) -2-oxo-l-azetidinyl] - 2-chloroacetic acid-acetonylester.

A solution of 1.54 g of 2 - [(4S) -4- (cis-2-carbo- (l) -menthyloxyvinylthio) - 2 -oxo-l-azetidinyl] - 2-hydroxyacetic acid-acetonylester in, cooled to - 15 ° 15 ml of dry tetrahydrofuran are mixed with stirring with 0.26 ml (3.6 mM) of thionyl chloride and within 5 minutes with a solution of 0.5 ml (3.6 mM) of triethylamine in 1.5 ml of tetrahydrofuran. The reaction mixture is continued for 15 minutes at 0 °, mixed with 100 ml of cold methylene chloride and washed with 30 ml of ice-cold aqueous hydrochloric acid. The organic phase is dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on 40 g silica gel with toluene-ethyl acetate 1: 1 and gives the title compound. IR spectrum (in CH2C12): absorption bands at 3.4; 5.6; 5.75; 5.9; 6.3; 8.2; 8.5 p.

Example 86

2 - [(4R) -4- (ice-2-Carbo- (1) -menthyloxyvinylthio) -2-oxo-l-azetidinyl] - 2-chloroacetic acid-acetonylester.

Analogously to Example 85, the (4R) isomer is prepared starting from 2 - [(4R) -4- (cis-2-carbo- (l) -menthyloxyvinylthio) -2-oxo-l-azetidinyl] - 2-hydroxyacetic acid acetonylester . IR spectrum (in CH2C12): absorption bands at 3.4; 5.6; 5.75; 5.9; 6.3; 8.2; 8.5

Example 87

2- [(4S) -4- (trans- 2 -carbo- (1) -menthyloxyvinylthio) -2-oxo-1-azetidinyl] - 2-chloroacetic acid-acetonylester.

Analogously to Example 85, starting from 2 - [(4S) -4- (trans-2-carbo- (l) -menthyloxy-vinylthio) - 2-oxo-l-azetidinyl] - 2-hydroxyacetic acid-acetonylester, the (4S) - trans isomers produced. IR spectrum (in CH2C12): absorption bands at 3.4; 5.6; 5.75; 5.9; 6.3; 8.2; 8.5 p ..

Example 88

2- [(4R) -4- (trans- 2 -carbo- (1) -menthyloxyvinylthio) -2-oxo-l-azedidinyl] - 2-chloroacetic acid-acetonylester.

Analogously to Example 85, starting from 2 - [(4R) -4- (cis-2-carbo- (l) -menthyloxyvinylthio) -2-oxo-l-azetidinyl-2-hydroxyacetic acid-acetonylester, the (4R) -trans isomer produced. IR spectrum (in CH2C12): absorption bands at 3.4; 5.6; 5.75; 5.9; 6.3; 8.2; 8.5 yes.

Example 89

2- [(4S) -4- (eis-2-carbo- (1) -menthyloxyvinylthio) -2-oxo-1-azetidinyl] - 2-triphenylphosphoranylidene-acetic acid-acetony ester.

A solution of 1.40 g (3.3 mM) of 2 - [(4S) -4-cis- 2-carbo- (l) -menthyloxyvinylthio) - 2-oxo-1-azetidinyl] - 2-chloroacetic acid- Acetonylester in 2.5 ml dry tetrahydrofuran is mixed with 1.57 g (6 mM) triphenylphosphine and left to stand at room temperature in a nitrogen atmosphere for 24 hours. The reaction mixture is diluted with 50 ml of methylene chloride, washed with 20 ml of cold, saturated aqueous sodium bicarbonate solution, over

32

Dried sodium sulfate and evaporated in vacuo. The residue is chromatographed on 40 g of silica gel with toluene / ethyl acetate 1: 1 and 1: 2 and gives the title compound which is contaminated with about 10% of the corresponding 5 trans compound which runs faster. IR spectrum (in CH2C12): absorption bands at 5.7; 5.9; 6.15; 6.85 | i; NMR spectrum (inCDCl3 / 100Mc; inppm): 5.9, d, 1H, J = 10Hz (ROOC-CH =).

10 Example 90

2 - [(4R,) - 4- (eis-2-carbo- (1) menthyloxyvinylthio) -2-oxo-1-azetidinyl] - 2 -triphenylphosphoranylideneacetic acid-acetony ester.

Analogously to Example 89, starting with 2 - [(4R) -4- (cis-15 2-carbo- (l) -menthyloxyvinylthio) -2-oxo-l-azetidinyl] -2-chloroacetic acid-acetonylester, the (4R) -cis Isomers produced. IR spectrum (in CH2C12): absorption bands at 5.7; 5.9; 6.15; 6.85 | i. NMR spectrum: same bands as in Example 89.

20th

Example 91

2- [(4S) -4- (trans- 2 -carbo- (1) -menthyloxyvinylthio) - 2 -oxo-l-azetidinyl] - 2 -triphenylphosphoranylidene-acetic acid-acetonylester.

25 Analogously to Example 89, starting with 2 - [(4S) -4- (trans-2-carbo- (l) -menthyloxyvinylthio) - 2-oxo-l-azetidinyl] - 2-chloroacetic acid-acetonylester, the (4S) -trans Isomers produced. IR spectrum (in CH2C12): absorption bands at 5.7; 5.9; 6.15; 6.85 (i; NMR spectrum (in CDC13 / 100 Mc; in 30 ppm): 5.8, d, IH, J = 15 Hz (ROOC-CH =).

Example 92

2-] (4R) -4- (trans- 2 -carbo- (1) menthyloxyvinylthio) -2 -35 oxo-l-azetidinyl] -2-triphenylphosphoranylidene-acetic acid-acetony ester.

Analogously to Example 89, starting from 2 - [(4R) -4-trans-2-carbo- (l) -menthyloxyvinylthio) - 2-oxo-l-azetidinyl] - 2-chloroacetic acid-acetonylester, the (4R) -trans isomer Herge-40 places. IR spectrum (in CH2C12) absorption bands at 5.7; 5.9; 6.15; 6.85 p .; NMR spectrum same bands as in Example 91 '.

Example 93

45 (5S) -2 -penem-3-carboxylic acid acetonylester.

A solution of 1.38 g (2 mM) of 2 - [(4S) - (cis- 2 -carbo- (l) -menthyloxyvinylthio) - 2 -oxo-l-azetidinyl] - 2 -triphenylphos-phoranylidene-acetic acid acetone ester in 30 ml of dry methylene chloride is mixed at -20 ° with 1 ml of trifluoroacetic acid 50, after which an ozone-oxygen stream (0.33 mM 03 / minute) is passed through for 10 minutes. The ozonizing solution is flushed with nitrogen, 1.5 ml of dimethyl sulfide are added and, after warming to room temperature, shaken with 30 ml of methylene chloride and 60 ml of cold, saturated, aqueous sodium bicarbonate solution. The organic phase is separated off, washed again with 15 ml of cold, saturated, aqueous sodium hydrogen carbonate solution, dried over sodium sulfate and evaporated in vacuo. The colorless foam, containing the 2 - [(4S) 4-form-60 ylthio-2-oxo-l-azetidinyl] - 2 -triphenyl-phosphoranylidene-acetic acid-acetonylester, is dried under high vacuum, in 50 ml of dry, acid-free methylene chloride heated under reflux in an argon atmosphere for 75 minutes and freed from the solvent in vacuo. The residue is chromatographed 65 on 20 g of silica gel with toluene-ethyl acetate 3: 1 and gives the title compound which has a melting point of 105-107 °, recrystallized from methylene chloride-diethyl ether-pentane; IR spectrum (in CH2C12): absorption bands

33

646173

at, 5.55; 5.75 (sh); 5.8; 6.4; 8.25; 8.5 [i; NMR spectrum (in CDClj / 100 Mc; in ppm); 2.2.3H, s; 3.7.2H, m; 4,8,2H, s; 5.8,? N

1H, m; 7.4.1H; s; [a] ^ = -249 ° ± 0.5 ° (c = 1%; CHC13).

The same compound is obtained if 2 - [(4S) - (trans-2-carbo- (l) -menthyloxyvinylthio) - 2 -oxo-1-azetidinyl] - 2 -triphenylphosphoranylidenacetic acid-acetonylester is reacted in an analogous manner.

Example 94

(5R) -2-penem-3-carboxylic acid acetonylester.

Analogously to Example 93, starting from 2 - [(4R) - (cis- 2-carbo- (l) -menthyloxyvinylthio) - 2-oxo-l-azetidinyl] - 2-tri-phenylphosphoranylideneacetic acid-acetonylester, the (5R) - Title connection established. Melting point 93-94 °; IR spectrum (in CH2C12): absorption bands at 5.55; 5.8; 6.4; 8.25; 8.5 | i; NMR spectrum (in CDC13 / 100 Mc; in ppm): 2.2.3H,

s; 3.7.2H, m. 4.8; 2H; s; 5.8.1H; m; 7.4.1H, s; [a] ^ = +

251 ° ± 1 ° (c = 1%; CHCI3).

The same compound is obtained when the 2 - [(4R) - (trans-2-carbo- (l) -mentyloxyvinylthio) - 2-oxo-l-azetidino-nyl] -2-triphenylphosphoranylidene-acetic acid-acetonylester in an analogous manner is implemented.

Example 95

(5S) -2 -penem-3-carboxylic acid.

A solution of 91 mg (0.4 mM) (5S) - 2 -penem-3-carbonic acid-acetonylester in 9 ml of tetrahydrofuran and 1 ml of water is at 0 ° within 15 minutes with 4 ml of 0.1 N aqueous sodium hydroxide solution added dropwise and stirred for a further 30 minutes at the same temperature. The reaction mixture is diluted with 4 ml of water, washed with 8 ml of diethyl ether and shaken with 80 ml of methylene chloride and 2 ml of 20% aqueous citric acid. The organic phase is dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on 4 g of silica gel with methylene chloride-glacial acetic acid 9: 1. The fractions containing the title compound are evaporated together with toluene in a high vacuum and give the crystalline product of melting point> 300 °; IR spectrum (in CH2C12): absorption bands at 5.55; 5.9; 6.4 h;

[a] p. - 383 ° (c = 1%; CH2C12).

Example 96

(5RJ-2 -penem earbonic acid.

Analogously to Example 95, starting from (5R) - 2 -penem-3-carboxylic acid acetonylester, the (5R) title compound is obtained. Melting point> 300 °; IR spectrum (in CH2C12): absorptive

20th

tion bands at 5.55; 5.9; 6.4 yes; [a] ^ = + 384 ° ± 1 ° (c = 1%; CH2C12).

Example 97

Penicillanic acid methyl ester l-oxide.

A solution of 6.5 g of methyl penicillanate (prepared by catalytic hydrogenation of methyl 6a-bromo-penicillanate using 5% palladium / barium carbonate catalyst in aqueous dioxane) in 220 ml of methylene chloride is cooled to -15 ° under nitrogen with a solution of 6.14 g of 85% m-chloroperbenzoic acid (30.23 mM) in 140 ml of methylene chloride was added dropwise and stirring was continued for 2 hours at the same temperature. The reaction mixture is diluted with methylene chloride, washed successively with 3% aqueous sodium bisulfite and 8% aqueous sodium bicarbonate solution and dried over sodium sulfate. The solvent is evaporated in vacuo and the residue in this crude form is used in the next reaction. A sample is chromatographed on silica gel (10% H20). With toluene-ethyl acetate 2: 1, the title compound is obtained in the form of an oil, which 5 follows after another thin-layer chromatographic purification on silica gel plates with toluene-ethyl acetate 1: 1

20th

has physico-chemical properties: [a] = + 280 ° ± 10

(c = 1.005% in CHCI3); IR spectrum (in methylene chloride): 10 characteristic absorption bands at 3.25-3.50; 5.61; 5.72; 6.86; 7.00; 7.10 (sh); 7.21; 7.32; 7.42; 7.81-8.01 (broad); 8.22 sh; 8.30-8.36; 8.47 (sh); 9.21; 9.46; 9.88 (sh); 9.96 h; NMR spectrum (in CDCI3 / IOO Mc; in ppm: 1.23.3H, s; 1.70.3H, s; 3.34.2H, d; 3.80.3H, s; 4.51.1H , s; 4.97.1H, t.

15

Example 98

Methyl 2- [(4R) -4-benzothiazole-2-yldithio) -2-oxoazetidin-l-yl] -3-methylene butyrate.

A solution of 685 mg methyl penicillanate 1-20 oxide and 496 mg (2.97 mM) 2-mercaptobenzothiazole in 30 ml toluene is heated under reflux for 2.5 hours. The solvent is distilled off in vacuo and the residue is chromatographed on 60 g of silica gel. The title compound is obtained in amorphous form by elution with toluene / ethyl acetate 9: 1. TLC: Rf = 0.47 (ethyl acetate-toluene 1: 1); IR spectrum (in methylene chloride): absorption bands at 5.66; 5.75; 5.97-6.05 ;, 6.75 (sh); 6.84; 7.03; 7.28; 7.53; 7.60

(sh); 7.65 (sh); 8.10; 8.35; 8.50; 8.89; 9.25; 9.81; 9.93] i; [a] ?? 30 = - 392 ° ± 1 ° (c = 0.777% in CHC13).

Example 99

2- [(4R) -4- (benzothiazole-2-yldithio) - 2-oxoazetidin-l-ylJ-3-methyllerotonic acid methyl ester.

35 ml of a solution of 12 g of 2 - [(4R) -4-benzothiazol-2-yldithio) -2-oxoazetidin-l-yl] -3-methylenebutyric acid methyl ester in 500 ml of methylene chloride is added and the mixture is left to stand at room temperature for 90 minutes calmly. The reaction mixture is washed with 5% aqueous citric acid solution, dried over sodium sulfate and freed from the solvent in vacuo. The residue is deactivated by chromatography on silica gel (deactivated with 10% water) with toluene and toluene-ethyl acetate 19: 1 and gives the title compound which, after recrystallization 45 from diethyl ether-pentane, has a melting point of 63-66 °. TLC: Rf = 0.44 (ethyl acetate-toluene 1: 1); IR spectrum (in methylene chloride): characteristic absorption bands at 3.35-3.60; 5.66; 5.81; 5.87 (sh); 5.93 (sh); 6.15; 6.85; 7.04; 7.26; 7.36; 7.65 (sh); 7.73; 8.17; 8.25 (sh); 8.35 (sh); 8.90; so 9.18 (sh); 9.26; 9.42 (sh); 9.81 (sh); 9.92; 10.25; 10.95 (broad) h;

[a] p = -153 ° ± 1 ° (c = 0.916%; in CHC13).

Example 100

55 2- [(4R) -4-acetylthio-2-oxoazetidin-l-yl) -3-methylenero-tonsonic acid methyl ester.

i) A solution of 4.6 g of 2 - [(4R) -4- (benzothiazol-2-yldithio) - 2 -oxoazetdin-l-yl] -3 ~ methylcrotonic acid methyl ester in 120 ml of dimethylformamide is cooled to - 20 ° , with a solution of 670 mg of sodium borohydride in 80 ml of dimethylformamide and stirred at the same temperature for 10 minutes. The temperature of the reaction mixture is raised to 0 ° for 60 minutes, then cooled again to −20 °, whereupon 40 ml of freshly distilled acetyl bromide are added dropwise and stirring is continued at 0 ° for 2 hours. After addition of 1.51 benzene, the reaction mixture is washed successively with ice water, water, 8% aqueous sodium carbonate solution and water, over sodium

646 173

34

dried sulfate and evaporated in vacuo. After chromatography on silica gel (deactivated with 10% water) with toluene and toluene-ethyl acetate 19: 1, the residue gives the title compound which is somewhat contaminated by the (4S) -enantiomer. Repeated chromatography and recrystallization from diethyl ether-pentane gives the pure title compound

20th

from melting point 81-82 ° [a] ^ = + 149 ° ± 1 (c = 0.994%;

CHCI3); TLC: Rf = 0.40 (ethyl acetate-toluene 1: 1); IR spectrum (in methylene chloride): absorption bands at 3.35-3.57; 5.66; 5.81; 5.89; 5.96 (sh); 6.15; 7.00; 7.07; (sh); 7.25; 7.35; 7.72; 8.15; 8.22 (sh); 8.35 (sh); 8.86; 9.15; 9.26; 9.42; 9.95; 10.11; 10.50 (broad); 10.80 | i.

ii) The partial racemization can be prevented by the following procedure:

To a solution of 380 mg (1 mM) of 2 - [(4R) -4- (benzothiazol-2-yldithio) -2-oxoazetidin-l-yl] -3-methylcrotonic acid methyl ester in 3 ml of acetic anhydride, stirred under nitrogen and in an ice bath and 5 ml of glacial acetic acid are given in portions of 1 g of zinc powder within one hour. The reaction mixture is stirred for one hour at room temperature, filtered and evaporated in vacuo. The residue is taken up in methylene chloride and washed successively with 25% aqueous ammonium chloride solution and aqueous sodium hydrogen carbonate solution. The combined aqueous phases are re-extracted with methylene chloride, all methylene chloride phases are combined, dried with sodium sulfate and evaporated in vacuo. The residue is chromatographed on 40 g of silica gel (deactivated with 10% water) with toluene and toluene-ethyl acetate 19: 1 and gives the optically pure title compound of

Melting point 78-80 °; [a] J? = + 149 ° ± 10 (c = 1.007%; in CHCL3). U

Example 101

Methyl 2- [(4R) -4-acetylthio-2-oxoazetidin-l-yl) -2-oxoacetic acid.

4 equivalents of ozone are introduced into a solution of 150 mg of 2 - [(4R) -4-acetylthio-2-oxoazetidin-l-yl] -3-methylenecrotonic acid methyl ester in 3 ml of methanol cooled to −15 ° within 60 minutes. The reaction mixture is flushed with nitrogen, diluted with methylene chloride and washed with a 5% aqueous sodium sulfite solution for 2 minutes. The organic phase is dried over sodium sulfate and evaporated in vacuo. IR spectrum of the oily title compound obtained (in methylene chloride): characteristic bands at 3.30-3.40; 5.52; 5.70; 5.83 (sh); 5.86; 6.98; 7.08 (sh); 7.40; 7.82-8.00 (broad, sh); 8.07; 8.19; 8.30 (sh); 8.46; 8.90; 9.22; 9.52; 9.91; 10.30; 10.73 ji. The product obtained can be used in the next step without further purification.

Example 102

(4R) -4-ethylthio-2-oxoazetidine.

A solution of 140 mg of methyl 2 - [(4R) -4-acetylthio-2-oxoazetidin-l-yl) -2-oxoacetic acid (crude product) in a mixture of 20 ml of methanol, 2 ml of methyl acetate and 0.4 ml of water is left to stand at room temperature for 20 hours, evaporated in vacuo and evaporated again with benzene. The residue is chromatographed on silica gel thick-layer plates with toluene-ethyl acetate 2: 1 and gives the title compound. TLC: Rf = 0.29 (ethyl acetate-toluene 1: 1); IR spectrum (in methylene chloride): characteristic absorption bands at 2.98; 5.62; 5.91; 7.13; 7.41 (sh); 7.46; 7.83-8.15 (broad); 8.62; 8.89; 9.07 (sh); 9.20 (sh); 10.19; 10.58;

11.05-11.15 (broad) \ i. [a] jL ° = + 359 ° ± 1 ° (c = 0.947%; in CHCI3) ..

Example 103

2 - [(4R) -4-acetylthio-2-oxoazetidin-l-yl] - 2-hydroxyesacetic acid-p-nitrobenzyl ester.

A solution of 54.5 mg (3S, 4R) -4-acetylthio-3-meth-5 oxy-2-oxoazetidine in a mixture of 4 ml of toluene and 1 ml of dimethylformamide is mixed with 200 mg of 2-ethoxy-2-hydr. p-nitrobenzyl oxy-acetic acid and 2 g of molecular sieve A4 were added and the mixture was stirred at 50 ° for 2 hours. The molecular sieves are filtered off and the filtrate is evaporated in vacuo. The residue is chromatographed on silica gel, whereby the title compound, contaminated with some glyoxylate, is obtained by elution with toluene / ethyl acetate 9: 1. TLC: Rf = 0.48 (ethyl acetate); IR spectrum (in CH2C12): absorption bands at 2.89 (broad); 5.64; 5.73; 5.91; 6.24; 6.56; 15 7.44; 7.62; 7.83-8.15 (broad sh); 8.26; 8.39; 8.80-9.30 (broad) \ i.

Example 104

2- [(4R) -4-acetylthio-2-oxoazetidin-l-yl] - 2-triphenyl-phosphoranylidene-acetic acid-p-nitrobenzyl ester. 20 a) To a suspension of 12 g of poly-Hunig base stirred at room temperature in a solution of 2.83 g (7.59 mM) of 2 - [(4R) -4-acetylthio-2-oxoazetidine -1-yl] - 2 - Hydroxy-acetic acid p-nitrobenzyl ester in 100 ml of dioxane, a solution of 2.86 g (~ 24 mM) of thionyl chloride in 20 ml of dioxane 25 is added dropwise. The mixture is stirred for 1.5 hours at room temperature, filtered off from the poly Hunig base, which is washed with dioxane. The filtrate is evaporated in vacuo. The 2 - [(4R) -4-acetylthio-2-oxoazetidin-1-yl] - 2-chloroacetic acid p-nitrobenzyl ester obtained is used in crude form in the next step.

b) A solution of 3.1g of 2 - [(4R) -4-acetylthio-2-oxoaze-tidin-l-yl] - 2-chloroacetic acid-jp-nitrobenzyl ester in 120 ml of dioxane is mixed with 3.144 g (~ 1.5 Equivalents) of triphenylphosphine and 12 g of poly-Hünig base and stirred for 17 hours under 35 nitrogen at 50 °. The poly-Hunig base is filtered off, washed with dioxane and the filtrate is evaporated in vacuo. The residue is chromatographed twice on silica gel with toluene and toluene-ethyl acetate 4: 1 and 3: 2 and gives the title compound. TLC: Rf = 0.21 (ethyl acetate: 40 toluene 1: 1); IR spectrum (in methylene chloride): characteristic absorption bands at 3.30-3.55; 5.70; 5.90; 6.05 (sh); 6.09 (sh); 6.16; 6.22 (sh); 6.57; 6.74; 6.96; 7.05 (sh); 7.20;

7.44; 7.80-8.05 (broad); 8.25; 8.40; 8.85; 9.05; 9.25 h; [a] ?? = 45 + 35 ° db 1 ° (c = 1.061% in CHCI3).

Example 105

(5R) -2-methyl-2-penem-3-carboxylic acid p-nitrobenzyl ester.

A solution of 500 mg (4R) - 2 - [4-acetylthio-2-oxo-azetidin-1-yl] - 2 -triphenylphosphoranyliden-acetic acid-p-nitrobenzyl ester in 500 ml of absolute toluene is mixed with a catalytic amount of hydroquinone and 40 Stirred for hours at 90 ° under argon. The toluene is evaporated in vacuo and the residue is chromatographed on 20 g of silica gel with toluene-ethyl acetate 19: 1. The title compound is obtained in crystalline form. Melting point: 147.5-149.5 ° (from methylene chloride diethyl ether); DC: Rf =

so 0.54 (ethyl acetate-toluene 1: 1); [a]? J = + 136 ° ± 1 ° (c = 1.034%; in CHC13); IR spectrum: absorption bands at 3.40-3.55; 5.59; 5.84; 5.95 (sh); 6.22 (sh); 6.30; 6.55; 7.15; 7.28; 7.41; 7.61; 7.69 (sh); 8.28; 8.35; 8.56; 8.63 (sh); 9.02 (sh); 9.10; 9.25; 9.43; 9.62; 9.84 ju

65

Example 106

(5R) -2-methyl-2-penem-3-earbonic acid.

A solution of 100 mg (5R) - 2-methyl-2-penem-3-car-

35

646173

Bonic acid p-nitrobenzyl ester in a mixture of 6 ml of ethyl acetate and 4 ml of 0.2 M sodium bicarbonate solution is mixed with 140 mg of 10% palladium / carbon catalyst and hydrogenated under atmospheric pressure for 30 minutes at room temperature. After adding a further 70 mg of catalyst 5, the mixture is hydrogenated again for 30 minutes. The hydrogenation mixture is filtered through diatomaceous earth, the filter residue is washed with 2 ml of 0.2 M aqueous sodium bicarbonate solution and methyl acetate. The aqueous phase is separated from the filtrate, washed with methylene chloride, acidified with 5% aqueous citric acid and extracted several times with methylene chloride. The combined methylene chloride extracts are dried over sodium sulfate, evaporated in vacuo and recrystallized from acetone at - 20 °. Melting

20 "15

point 142-145 ° (decomposition); [a] ^ = + 286 ° ± 1 (c =

0.603%; in acetone); IR spectrum (in KBr): absorption bands at 2.85-4.30 (broad); 5.60 (sh); 5.66; 5.97 (sh); 6.04; 6.42; 6.50 (sh); 7.05 (broad); 7.32; 7.64 (broad); 7.80 (broad); 8.17-8.25 (broad); 8.40 (i; NMR spectrum (in df) -acetone / 100 Mc; in 20 ppm): 2.31.3H, s; 3.39.1H, dd, J, = 16Hz, J2 = 2Hz; 3.82; 1H, dd, J, = 16Hz, J3 = 4Hz; 5,69,1H, dd, J2 = 2Hz, J3 = 4Hz.

Example 107

(4R, S) -4- (Nicotinoylthio) -2-oxo-azetidine. 25th

A solution of 5.16 g (4R, S) -4-acetoxy-azetidin-2-one in 30 ml water is added dropwise under nitrogen at room temperature with a solution of 6.95 thionicotinic acid in 50 ml IN sodium hydroxide solution (a small excess - Shot of sodium hydroxide solution is added to keep the solution near pH8) and stirred at the same temperature for 1 hour. The reaction mixture is extracted exhaustively with methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel with toluene / ethyl acetate 2: 3 to give the title compound of melting point 112-113 °. TLC: Rf = 0.14 (toluene-ethyl acetate 2: 3), IR spectrum (CH2C12): absorption bands at 2.95; 5.6; 5.97; 6.27; 8.15; 8.2; 10.85; 11.12 p.

40

Example 108

2 - [(4R, S) -4- (nicotinoylthio) -2-oxo-l-azetidinyl] -2-hydroxyacetic acid p-nitrobenzyl ester.

At room temperature, 1 g (4.8 mM) (4R, S) -4- (Ni-cotinoylthio) - 2-oxo-azetidine with a solution of 3 g of 2- 45 ethoxy-2-hydroxy-acetic acid p-nitrobenzyl ester in 60 ml of dry toluene and 15 ml of dry dimethylformamide. After adding freshly dried molecular sieves, the mixture is stirred under nitrogen for 15 hours at room temperature and then for 2 hours at 50 °. The molecular sieves are filtered off, washed with toluene and the filtrate and washing liquid are evaporated together in vacuo. The residue is chromatographed on 200 g of silica gel with toluene / ethyl acetate 9: 1 to 6: 4. After elution of unreacted 2-ethoxy-2-hydroxy-acetic acid-55-acid-p-nitro-benzyl ester, the title compound is eluted with the following physicochemical properties: TLC: Rf = 0.13 (toluene-ethyl acetate 2: 3); IR spectrum (CH2C12): absorption bands at 5.62.5.7; 6.0; 6.55; 7.4 and 8.22 (i.

60

Example 109

2- [(4R, S) -4-nicotinoylthio) - 2-oxo 1-azetidinyl] - 2-tri-phenylphosphoranylidene-acetic acid-p-nitrobenzyl ester.

a) A solution of 3.6 g (8.64 mM) 2 - [(4R, S) -4- (Nicotinoylthio) - 2-oxo-l-azetidinyl] - 2-hydroxyacetic acid-p-nitro-6s Benzyl ester in 60 ml of absolute dioxane is added to a solution of 13 g of poly-Hunig base in 30 ml of absolute dioxane which has already been stirred for 30 minutes. After adding a solution of 2.5 ml of thionyl chloride in 24 ml of absolute dioxane, the reaction mixture is stirred for one hour at room temperature and under nitrogen. The poly-Hunig base is filtered off, washed with dioxane and the filtrate and washing liquid are evaporated in vacuo.

b) The crude 2 - [(4R, S) -4 - (, icotinoylthio) - 2 -oxo-l-azetidinyl] - 2-chloroacetic acid p-nitrobenzyl ester obtained is dissolved in 150 ml of absolute dioxane and together with 12.9 g of poly Hunig base and 4.5 g of triphenylphosphine stirred overnight at 50 ° under nitrogen. The poly Hunig base is filtered off, washed with dioxane and the filtrate and washing liquid are evaporated together in vacuo. The residue is chromatographed on 150 g silica gel with toluene-ethyl acetate 8: 2 to 6: 4 and gives the title compound with the following physicochemical properties: TLC: Rf = 0.1 (toluene-ethyl acetate 2: 3); IR spectrum (CH2C12): absorption bands at 5.67; 6.0; 6.15; 6.55; 6.95; 7.4; 8.2; 9.05;

9.25 n

Example 110

(5R, S) - 2-pyrid-3-yl-2-penem-3-earbonic acid p-nitro-benzyl ester.

A solution of 2.15 g of 2 - [(4R, S) -4- (nicotinoylthio) - 2-oxo-l-azetidinyl] - 2-triphenylphosphoranylidene acetic acid pnitrobenzyl ester in 1 liter of absolute toluene is mixed with a catalytic amount of hydroquinone and stirred under nitrogen at 90 ° for 24 hours. The solvent is evaporated in vacuo and the residue is chromatographed on 100 g of silica gel with toluene-ethyl acetate 3: 2. The title compound is obtained in the form of yellowish crystals with the following physicochemical properties: Melting point: 160-161 ° (diethyl ether-methylene chloride); TLC: Rf = 0.21 (toluene-ethyl acetate 2: 3); UV spectrum (in ethanol): Àmax = 333 nm (s = 6678); 259 nm (e = 15 526), IR spectrum (CH2C12): absorption bands at 5.55; 5.78; 6.55; 7.4; 7.6; 8.35 and 8.5 n; Nuclear Magnetic Resonance Spectrum (in CDCI3 / 100 Mc; in ppm): 8.7-8.6.2H, m; 8.16.2H, m; 7.78.1H, m; 7.5-7.25.3H, m; 5.84.1H, m; 5.24.2H, m; 4.04-3.5.2H, m.

Example 111

(5R, S) -2-pyrid-3-yl-2 -penem-3-carboxylic acid.

A solution of 50 mg (0.13 mM) (5R, S) - 2-pyrid-3-yl-2 -penem-3-carboxylic acid p-nitrobenzyl ester in 3 ml of absolute ethyl acetate is mixed with 2 ml of water and 100 mg of 10 % Palladium / carbon catalyst and stirred at normal pressure for 50 minutes under hydrogen. The hydrogenation mixture is filtered off from the catalyst over diatomaceous earth and the filtrate is washed with water, ethyl acetate and again with water. The combined aqueous phases are freeze-dried. The title compound obtained has the following physicochemical properties: UV spectrum (in ethanol): A.max = 316 nm; IR spectrum (KBr): absorption bands at 7.9.1H, m, 7.6.1H, m; 2.95; 5.65; 6.2; 7.3 \ i.

Example 112

The following compounds can be obtained in an analogous manner and using the appropriate intermediates and, if appropriate, with the liberation of functional groups:

(5R, S) - 2-methyl-2-penem-4-carboxylic acid tert-butyl ester; TLC: Rf = 0.63 (toluene-ethyl acetate 1: 1); IR spectrum (CH2C12): absorption bands at 3.9; 5.6; 5.85; 6.25; 7.3; 7.55; 8.65 ^ .;

(5R, S) - 2-ethyl-2-penem-3-carboxylic acid; (5R, S) - 2-isopropyl-2-penem-3-carboxylic acid; (5R, S) - 2-hydroxymethyl-2-penem-4-carboxylic acid;

646 173 36

(5R, S) - 2-acetoxyethyl-2-penem-3-carboxylic acid; and Example 114

(5R, S) - 2-hydroxyethyl-2-penem-3-carboxylic acid; Capsules containing 0.25 g of (5R, S) - 2-methyl-2-pen-

as well as the corresponding (5R) and (5S) connections; and em-3-carboxylic acid are prepared as follows:

their salts. Composition (for 1000 capsules)

s 5 (R, S) - 2-methyl-2-penem-3-carboxylic acid 250,000

Example 113 Corn starch 50,000 g

Dry ampoules or vials containing 0.5 g of sodium polyvinylpyrrolidone 15,000 g of salt of (5R, S) - 2-methyl-2-penem-3-carboxylic acid, magnesium stearate 5,000 g are produced as follows: ethanol q.s. Composition (for 1 ampoule or vial) 10

Sodium salt of (5R, S) - 2-methyl-2-penem-die (5R, S) - 2-methyl-2-penem-3-carboxylic acid and

3-carboxylic acid 0.5 g corn starch are mixed and mixed with a solution of the poly-

Mannitol moistened with 0.05 g vinyl pyrrolidone in 50 g ethanol. The damp

• The mass is pressed through a sieve with a mesh size of 3 mm. A sterile aqueous solution of the sodium salt of 15 and dried at 45 °. The dry granulate is (5R, S) - 2-methyl-2-penem-3-carboxylic acid and the mannitol is passed through a sieve with a mesh size of 1 mm is mixed under aseptic conditions in 5 ml ampoules or and with 5 g magnesium stearate . The mixture is subjected to 5 ml. Vials of freeze-drying and the Am in 0.320 g portions in size 0 plug-in capsules or vials sealed and checked. filled.

C.

Claims (19)

646 173 PATENT CLAIMS 1,2-Penem-3-carboxylic acid compounds of the formula (I), (1) 55 60 wherein R] and R2 have the meanings given in claim 14, and salts of such compounds with salt-forming groups, characterized in that a compound of formula I is treated with a suitable oxidizing agent. 65 1 0 = i-R " ./" 1 20th H (I), 25 # r \, -, * T-R, (I), 0 = C-R. 35 wherein Ri stands for an organic radical connected via a carbon atom to the ring carbon atom or an etherified mercapto group which are substituted by 3-guanyl-ureido, and R2 has the meaning given in claim 14, and salts of such compounds with salt-forming groups, characterized in that that in a compound of formula I in which R] represents an organic radical connected via a carbon atom to the ring carbon atom or an etherified mercapto group which is substituted by an amino group, the amino group by reaction with the reaction mixture obtained by reaction of an acid addition salt a 4-guanyl semicarbazide with sodium nitrite, converted into a 3-guanylureido group, and optionally converting a salt-forming group compound obtained into a salt or a salt obtained into the free compound or another salt. 2,2-Penem-3-carboxylic acid compounds of the formula I, according to claim 1, in which R | Hydrogen, lower alkyl, by hydroxy, lower alkoxy, lower alkanoyloxy, halogen lower alkylthio, carboxyl, lower alkoxycarbonyl, carbamoyl, cyano, nitro, amino, mono- or di-lower alkylamino, lower alkyleneamino or aeylated amino-substituted lower alkyl, lower alkoxycarbonyl, aryl-lower alkoxycarbonyl-bonyl, aryl , Mono- or dinie deralkylaminocarbonyl, cycloalkyl, cycloalkyl-lower alkyl, phenyl, naphthyl, phenyl-lower alkyl, phenyl or phenyl-lower alkyl substituted by lower alkyl, lower alkoxy, halogen, nitro or amino, pyridyl, thienyl, furyl, pyridyl-lower alkyl, thienyl-lower alkyl, furyl-lower alkyl, lower alkyl, lower alkyl Cyclo-alkyl-lower alkylthio, phenylthio, phenyl-lower alkylthio, or substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, mercapto, lower alkylmercapto, carboxyl, lower alkoxy-40 carbonyl, carbamoyl, cyano, nitro, amino, mono- or di-lower alkylamino, acylamino or lower alkyleneamino Niederalkylthio, Niederalkenylthio, Cycloalkylthio, Cycloalkylniederalkylthio, Phenylthio or Phenyl-Niederalkylthio and R2 represents hydroxy or an etherified hydroxy group which can be split under neutral, basic or physiological conditions. 3rd 646173 where R | represents an organic radical connected via a carbon atom to the ring carbon atom or an etherified mercapto group which are substituted by sulfoamino, and R2 has the meaning given in claim 14 and salts of such compounds with salt-forming groups, characterized in that in a compound of Formula I, wherein R | represents an organic radical or an etherified mercapto group which is connected to the ring carbon atom via a carbon atom and which is substituted by an amino group, converts the amino group into a sulfoamino group by treatment with a complex of sulfur trioxide with an organic base, and optionally a compound obtained salt-balancing group converted into a salt or a salt obtained in the free compound or in another salt. 3.2-Penem-3-carboxylic acid compounds of formula (I), according to claim 1, wherein R is hydrogen, lower alkyl, 50 lower alkanoyloxy lower alkyl, lower alkylthio lower alkyl, lower alkoxycarbonyl lower alkyl, amino lower alkyl, aeylated amino lower alkyl, phenyl, benzyl, pyridyl, furyl, di-lower alkylaminophenyl or lower alkylthio and R2 is hydroxy. 4. (5 R, S) -2-methyl-2-penem-3-carboxylic acid according to claim 1. 5. (5R, S) -2-phenyl-2-penem-3-carboxylic acid according to claim 1. 6. (5R, S) -2-pentyl-2-penem-3-carboxylic acid according to claim 1. 7. (5R, S) -2-tert-butylthiomethyl-2-penem-3-carboxylic acid according to claim 1. 8. (5R, S) -2-ethylthio-2-penem-3-carboxylic acid according to patent claim 1. 9. (5R, S) -2-penem-3-carboxylic acid according to claim 1. wherein R] represents hydrogen, an organic radical connected via a carbon atom to the ring carbon atom or an etherified mercapto group, and R2 is hydroxyl or a radical RA2 forming an esterified carboxyl group —C (= O) - together with the carbonyl group, and salts thereof Compounds with salt-forming groups, characterized in that a ylide compound of the formula \ © -x © (ii), 55 o = c-r2 where Z represents oxygen or sulfur and R | and RA2 have the meanings given above, and in which X® denotes either a trisubstituted phosphoniogroup or a doubly esterified phosphonogroup together with a cation, optionally with ring protection with intermediate protection of the functional groups, and optionally a compound having a salt-forming group in a salt or a the salt obtained is converted into the free compound or into another salt. 10. (5R) -2-penem-3-carboxylic acid according to claim 1. 11. (5R) -2-methyl-2-penem-3-carboxylic acid according to claim 1. 12. Pharmaceutically acceptable salts of compounds of claims 1-11. 13. Pharmaceutical preparations containing one of the compounds claimed in claims 1-12. 14. A process for the preparation of 2-penem-3-carboxylic acid compounds of the formula in which R] is hydrogen, an organic radical linked via a carbon atom to the ring carbon atom or an etherified mercapto group, and R2 is hydroxy or one together with the carbonyl grouping —C (= O) - an esterified carboxyl group represents RA2, 1-oxides thereof, and salts of such compounds with salt-forming groups, in racemic and optically active form. 0: r * \ c-r, N \ / he 1 o «c-r2 (i). 15. The method according to claim 14, characterized in that a mixture of isomeric compounds of the formula I obtained is separated into the individual isomers. 16. A process for the preparation of 2-penem-3-carboxylic acid compounds of the formula c-r, (I), o-c-r, 17. Process for the preparation of 2-penem-3-carboxylic acid compounds of the formula H > r " - v / 1 a), S 0 = C-R io in which R, which has the meaning given in claim 14 and R2 is hydroxyl, characterized in that in a compound of the formula I, in which R, has the meaning given in claim 14 and R2 is a together with the carbonyl group -C (= O ) means an esterified carboxyl-i5 group radical RA2, which converts the esterified carboxyl group into the free carboxyl group. 20. Process for the preparation of compounds of the formula H / C-R, "\ 0 = C-R 18. A process for the preparation of 1-oxides of compounds of the formula in which R] has the meaning given in claim 14 and R2 is a radical RA2 which together with the carbonyl group -C (= O) forms an esterified carboxyl group, characterized in that in a compound of formula I, wherein R, which has the meaning given in claim 14 and R2 is hydroxy, converts the free carboxyl group into an esterified carboxyl group of the formula -C (= Ö) RA2. 40 50 H Q -i'8 " ; c-R, O 19. Process for the preparation of compounds of the formula